Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith

ABSTRACT

Provided herein are Aminopurine Compounds having the following structures: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , R 2 , and R 3  are as defined herein, compositions comprising an effective amount of an Aminopurine Compound, and methods for treating or preventing a cancer, for example, melanoma.

This application is a continuation of U.S. patent application Ser. No.16/514,749, filed Jul. 17, 2019, currently allowed, which is acontinuation of U.S. patent application Ser. No. 16/169,414, filed Oct.24, 2018, now U.S. Pat. No. 10,398,700, issued Sep. 3, 2019, which is adivisional of U.S. patent application Ser. No. 15/641,383, filed Jul. 5,2017, now U.S. Pat. No. 10,149,849, issued Dec. 11, 2018, which is acontinuation of U.S. patent application Ser. No. 15/335,619, filed Oct.27, 2016, now U.S. Pat. No. 9,737,541, issued Aug. 22, 2017, which is acontinuation of U.S. patent application Ser. No. 14/874,513, filed Oct.5, 2015, now U.S. Pat. No. 9,512,124, issued Dec. 6, 2016, which claimsthe benefit of U.S. Provisional Application No. 62/060,339, filed Oct.6, 2014, the entire contents of which are incorporated herein byreference.

FIELD

Provided herein are certain aminopurine compounds, compositionscomprising an effective amount of such compounds, and methods fortreating or preventing a cancer, for example, melanoma, comprisingadministering an effective amount of such aminopurine compoundscompounds to a subject in need thereof.

BACKGROUND

Melanoma is a cancer characterized by the uncontrolled growth ofpigment-producing cells (melanocytes). Malignant melanoma develops froma neoplastic transformation of melanocytes, which are predominantlyfound in the basal layer of the epidermis and the eye. (Spagnolo F etal., Archives of Dermatology Research, 2012, 304: 177-184; Hurst E A etal., Archives of Dermatology Research, 2003, 139: 1067-1073). Malignantmelanoma is the most aggressive form of skin cancer. In 2014, it isestimated that there will be 76,100 new cases of melanoma of the skinand an estimated 9,710 people will die of this disease. (SEER Stat FactSheets: Melanoma of the Skin, Surveillance Epidemiology and End ResultsProgram,—accessed on Jun. 2, 2014 athttp://seer.cancer.gov/statfacts/html/melan.html).

Although surgical removal of early melanoma lesions leads to a cure rateof 90%, advanced melanoma resists chemotherapy and tends to quicklymetastasize (Spagnolo F et al., Archives of Dermatology Research, 2012,304: 177-184); for these reasons, prognosis for advanced melanoma ispoor, with 5-year survival rates of 78% for patients with stage IIIA,59% for patients with stage IIIB, and 40% for patients with stage IIIC,respectively. (Balch C M et al., Journal of Clinical Oncology, 2009,27(36): 6199-6206). For patients with distant metastases, the prognosissignificantly worsens, with 1 year survival rates of 62% for stage M1a,53% for stage M1b and only 33% for stage M1c. (Balch C M et al., Journalof Clinical Oncology, 2009, 27(36): 6199-6206).

The treatment options for metastatic melanoma are limited. Prior to2011, only two therapies for metastatic melanoma had been approved bythe FDA: dacarbazine and high dose interleukin 2 (“HD IL-2”), neither ofwhich increased median overall survival. (Hill G et al., Cancer, 1984,53:1299-1305; Atkins M et al., Journal of Clinical Oncology, 1999,17(7): 2105-2116; Phan G et al., Journal of Clinical Oncology, 2001,19(15): 3477-3482). Moreover, dacarbazine is limited by a low responserate of 10% to 15%, while HD IL-2 has an even lower response rate of 6%to 10%. (Finn L et al., BMC Medicine, 2012, 10:23). During 2011, the FDAapproved two more therapies for advanced melanoma, vemurafenib(Zelboraf™) and ipilimumab. (Finn L et al., BMC Medicine, 2012, 10:23).While vemurafenib has demonstrated good clinical activity with a highresponse rate and low toxicity, its applicability is limited to the40%-60% of melanoma patients who harbor an activating mutation in theBRAF gene that leads to constitutive activation of the mitogen-activatedprotein kinase pathway (“MAPK”), which causes increased cellularproliferation as well as increased oncogenic activity. (Finn L et al.,BMC Medicine, 2012, 10:23). Additionally, most patients who initiallyrespond to treatment with BRAF inhibitors relapse, indicating thedevelopment of drug resistance and demonstrating the limitations oftargeting only one pathway to eradicate melanoma. (Villanueva J et al.,Cancer Cell, 2010, 18(6): 683-695; Spagnolo F et al., Archives ofDermatology Research, 2012, 304: 177-184). Ipilmumab can inducelong-term responses in a subset of patients, but its utility is limitedby its low response rate of 10% to 15% and by the fact that it improvesmedian survival time by only two months. (Finn L et al., BMC Medicine,2012, 10:23). Thus, there remains a serious need for additionaltherapies for treatment of melanoma.

Citation or identification of any reference in Section 2 of thisapplication is not to be construed as an admission that the reference isprior art to the present application.

SUMMARY

Provided herein are compounds having the following formula (I):

and pharmaceutically acceptable salts, tautomers, isotopologues, andstereoisomers thereof, wherein R¹, R² and R³ are as defined herein.

A compound of formula (I) or a pharmaceutically acceptable salt,tautomer, isotopologue, or stereoisomer thereof (each being referred toherein as an “Aminopurine Compound”) can be used in the methods providedherein. The compound of formula (I) or a pharmaceutically acceptablesalt, tautomer, isotopologue, or stereoisomer thereof is useful fortreating or preventing a cancer, for example, melanoma.

In one aspect, provided herein are Aminopurine Compounds as described inthe instant disclosure, such as, for example, in Table 1.

In one aspect, provided herein are pharmaceuticals comprising aneffective amount of an Aminopurine Compound as described herein, and apharmaceutically acceptable carrier, excipient or vehicle. In someembodiments the pharmaceutical composition is suitable for oral,parenteral, mucosal, transdermal or topical administration.

In one aspect, provided herein are methods for treating or preventingmelanoma, comprising administering to a subject in need thereof aneffective amount of an Aminopurine Compound as described herein; and apharmaceutically acceptable carrier, excipient or vehicle. In anotheraspect, provided herein are methods for treating or preventing melanoma,comprising administering to a subject in need thereof an effectiveamount of an Aminopurine Compound. The Aminopurine Compound as providedherein is for use in methods for treating or preventing melanoma,comprising administering to a subject in need thereof an effectiveamount of the Aminopurine Compound. The Aminopurine Compound as providedherein is for use in methods for treating or preventing melanoma,comprising administering to a subject in need thereof an effectiveamount of the Aminopurine Compound; and a pharmaceutically acceptablecarrier, excipient or vehicle.

In a further aspect, provided herein is a method of inhibiting a kinasein a cell expressing said kinase, comprising contacting said cell withan effective amount of the Aminopurine Compound as described herein. Themethod is an in vitro or an ex vivo method. Also provided is theAminopurine Compound for use in said methods.

In another aspect provided herein are methods for preparing AminopurineCompounds as described herein.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

DETAILED DESCRIPTION Definitions

An “alkyl” group is a saturated, partially saturated, or unsaturatedstraight chain or branched non-cyclic hydrocarbon having from 1 to 10carbon atoms, typically from 1 to 8 carbons or, in some embodiments,from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative alkylgroups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and-n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl,-2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyland the like. Examples of unsaturated alkyl groups include, but are notlimited to, vinyl, allyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂,—C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, —CC(CH₃), —CC(CH₂CH₃), —CH₂CCH,—CH₂CC(CH₃) and —CH₂CC(CH₂CH₃), among others. An alkyl group can besubstituted or unsubstituted. When the alkyl groups described herein aresaid to be “substituted,” they may be substituted with any substituentor substituents as those found in the exemplary compounds andembodiments disclosed herein, as well as halogen (chloro, iodo, bromo,or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino;carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine;guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine;thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester;urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine,aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide;isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)₂, orO(alkyl)aminocarbonyl.

A “cycloalkyl” group is a saturated, or partially saturated cyclic alkylgroup of from 3 to 10 carbon atoms having a single cyclic ring ormultiple condensed or bridged rings which can be optionally substitutedwith from 1 to 3 alkyl groups. In some embodiments, the cycloalkyl grouphas 3 to 8 ring members, whereas in other embodiments the number of ringcarbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkylgroups include, by way of example, single ring structures such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,2-methylcyclooctyl, and the like, or multiple or bridged ring structuressuch as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl and the like.Examples of unsaturared cycloalkyl groups include cyclohexenyl,cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl,among others. A cycloalkyl group can be substituted or unsubstituted.Such substituted cycloalkyl groups include, by way of example,cyclohexanol and the like.

An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl). In some embodiments, aryl groups contain6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms inthe ring portions of the groups. Particular aryls include phenyl,biphenyl, naphthyl and the like. An aryl group can be substituted orunsubstituted. The phrase “aryl groups” also includes groups containingfused rings, such as fused aromatic-aliphatic ring systems (e.g.,indanyl, tetrahydronaphthyl, and the like).

A “heteroaryl” group is an aryl ring system having one to fourheteroatoms as ring atoms in a heteroaromatic ring system, wherein theremainder of the atoms are carbon atoms. In some embodiments, heteroarylgroups contain 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to10 atoms in the ring portions of the groups. Suitable heteroatomsinclude oxygen, sulfur and nitrogen. In certain embodiments, theheteroaryl ring system is monocyclic or bicyclic. Non-limiting examplesinclude but are not limited to, groups such as pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl(e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl,pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl(e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridylor 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g.,1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl,benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g.,benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl),tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

A “heterocyclyl” is an aromatic (also referred to as heteroaryl) ornon-aromatic cycloalkyl in which one to four of the ring carbon atomsare independently replaced with a heteroatom from the group consistingof O, S and N. In some embodiments, heterocyclyl groups include 3 to10ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8ring members. Heterocyclyls can also be bonded to other groups at anyring atom (i.e., at any carbon atom or heteroatom of the heterocyclicring). A heterocycloalkyl group can be substituted or unsubstituted.Heterocyclyl groups encompass unsaturated, partially saturated andsaturated ring systems, such as, for example, imidazolyl, imidazolinyland imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl)groups. The phrase heterocyclyl includes fused ring species, includingthose comprising fused aromatic and non-aromatic groups, such as, forexample, 1-and 2-aminotetraline, benzotriazolyl (e.g.,1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g.,1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, andbenzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ringsystems containing a heteroatom such as, but not limited to,quinuclidyl. Representative examples of a heterocyclyl group include,but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl,pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl orimidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl,tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl,pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g.,benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl,oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl),morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g.,tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl,dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl,1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g.,indolyl-2-onyl or isoindolin-1-onyl), indolinyl, isoindolyl,isoindolinyl, azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl),indazolyl, indolizinyl, benzotriazolyl (e.g.1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g.,1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl,benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl,benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e.,benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl,benzo[1,3]dioxolyl, pyrazolopyridyl (for example,1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl(e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl,isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), quinolizinyl,quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl,pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one andtetrahydroquinolinyl groups. Representative non-aromatic heterocyclylgroups do not include fused ring species that comprise a fused aromaticgroup. Examples of non-aromatic heterocyclyl groups include aziridinyl,azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g.,imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl,thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl,piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl,tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl,oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl,quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representativesubstituted heterocyclyl groups may be mono-substituted or substitutedmore than once, such as, but not limited to, pyridyl or morpholinylgroups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstitutedwith various substituents such as those listed below.

A “cycloalkylalkyl” group is a radical of the formula:-alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.Substituted cycloalkylalkyl groups may be substituted at the alkyl, thecycloalkyl, or both the alkyl and the cycloalkyl portions of the group.Representative cycloalkylalkyl groups include but are not limited tomethylcyclopropyl, methylcyclobutyl, methylcyclopentyl,methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl,ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl and the like.

An “aralkyl” group is a radical of the formula: -alkyl-aryl, whereinalkyl and aryl are defined above. Substituted aralkyl groups may besubstituted at the alkyl, the aryl, or both the alkyl and the arylportions of the group. Representative aralkyl groups include but are notlimited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkylgroups such as 4-ethyl-indanyl.

An “heterocyclylalkyl” group is a radical of the formula:-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above.Substituted heterocyclylalkyl groups may be substituted at the alkyl,the heterocyclyl, or both the alkyl and the heterocyclyl portions of thegroup. Representative heterocylylalkyl groups include but are notlimited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl,furan-3-yl methyl, pyridin-3-yl methyl, tetrahydrofuran-2-yl ethyl, andindol-2-yl propyl.

A “halogen” is chloro, iodo, bromo, or fluoro.

A “hydroxyalkyl” group is an alkyl group as described herein substitutedwith one or more hydroxy groups.

An “alkoxy” group is —O-(alkyl), wherein alkyl is defined herein.

An “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is definedherein.

An “amine” group is a radical of the formula: —NH₂.

A “hydroxyl amine” group is a radical of the formula: —N(R^(#))OH or—NHOH, wherein R^(#) is a substituted or unsubstituted alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl orheterocyclylalkyl group as defined herein.

An “alkoxyamine” group is a radical of the formula: —N(R^(#))O-alkyl or—NHO-alkyl, wherein R^(#) and alkyl are as defined herein.

An “aryloxyamine” group is a radical of the formula: —N(R^(#))O-aryl or—NHO-aryl, wherein R^(#) and aryl are as defined herein.

An “aralkoxyamine” group is a radical of the formula: —N(R^(#))O-aralkylor —NHO-aralkyl, wherein R^(#) and aralkyl as defined herein.

An “alkylamine” group is a radical of the formula: —NH-alkyl or—N(alkyl)₂, wherein each alkyl is independently as defined herein.

An “aminocarbonyl” group is a radical of the formula: —C(═O)N(R^(#))₂,—C(═O)NH(R^(#)) or —C(═O)NH₂, wherein each R^(#) is as defined herein.

An “acylamino” group is a radical of the formula: —NHC(═O)(R^(#)) or—N(alkyl)C(═O)(R^(#)), wherein each alkyl and R^(#) are independently asdefined herein.

An “O(alkyl)aminocarbonyl” group is a radical of the formula:

—O(alkyl)C(═O)N(R^(#))₂, —O(alkyl)C(═O)NH(R^(#)) or —O(alkyl)C(═O)NH₂wherein each R^(#) and alkyl are independently as defined herein.

An “N-oxide” group is a radical of the formula: —N⁺—O⁻.

A “carboxy” group is a radical of the formula: —C(═O)OH.

A “ketone” group is a radical of the formula: —C(═O)(R^(#)), whereinR^(#) is as defined herein.

An “aldehyde” group is a radical of the formula: —CH(═O).

An “ester” group is a radical of the formula: —C(═O)O(R^(#)) or—OC(═O)(R^(#)), wherein R^(#) is as defined herein.

A “urea” group is a radical of the formula: —N(alkyl)C(═O)N(R^(#))₂,—N(alkyl)C(═O)NH(R^(#)), —N(alkyl)C(═O)NH₂, —NHC(═O)N(R^(#))₂,—NHC(═O)NH(R^(#)), or —NHC(═O)NH₂ ^(#), wherein each alkyl and R^(#) areindependently as defined herein.

An “imine” group is a radical of the formula: —N═C(R^(#))₂ or—C(R^(#))═N(R^(#)), wherein each R^(#) is independently as definedherein.

An “imide” group is a radical of the formula: —C(═O)N(R^(#))C(═O)(R^(#))or —N((C═O)(R^(#)))₂, wherein each R^(#) is independently as definedherein.

A “urethane” group is a radical of the formula: —OC(═O)N(R^(#))₂,—OC(═O)NH(R^(#)), —N(R^(#))C(═O)O(R^(#)), or —NHC(═O)O(R^(#)), whereineach R^(#) is independently as defined herein.

An “amidine” group is a radical of the formula: —C(═N(R^(#)))N(R^(#))₂,—C(═N(R^(#)))NH(R^(#)), —C(═N(R^(#)))NH₂, —C(═NH)N(R^(#))₂,—C(═NH)NH(R^(#)), —C(═NH)NH₂, —N═C(R^(#))N(R^(#))₂,—N═C(R^(#))NH(R^(#)), —N═C(R^(#))NH₂, —N(R^(#))C(R^(#))═N(R^(#)),—NHC(R^(#))═N(R^(#)), —N(R^(#))C(R^(#))═NH, or —NHC(R^(#))═NH, whereineach R^(#) is independently as defined herein.

A “guanidine” group is a radical of the formula:—N(R^(#))C(═N(R^(#)))N(R^(#))₂, —NHC(═N(R^(#)))N(R^(#))₂,—N(R^(#))C(═NH)N(R^(#))₂, —N(R^(#))C(═N(R^(#)))NH(R^(#)),—N(R^(#))C(═N(R^(#)))NH₂, —NHC(═NH)N(R^(#))₂, —NHC(═N(R^(#)))NH(R^(#)),—NHC(═N(R^(#)))NH₂, —NHC(═NH)NH(R^(#)), —NHC(═NH)NH₂, —N═C(N(R^(#))₂)₂,—N═C(NH(R^(#)))₂, or —N═C(NH2)₂, wherein each R^(#) is independently asdefined herein.

A “enamine” group is a radical of the formula:—N(R^(#))C(R^(#))═C(R^(#))₂, —NHC(R^(#))═C(R^(#))₂,—C(N(R^(#))═C(R^(#))₂, —C(NH(R^(#)))═C(R^(#))₂, —C(NH₂)═C(R^(#))₂,—C(R^(#))═C(R^(#))(N(R^(#))₂), —C(R^(#))═C(R^(#))(NH(R^(#))) or—C(R^(#))═C(R^(#))(NH₂), wherein each R^(#) is independently as definedherein.

An “oxime” group is a radical of the formula: —C(═NO(R^(#)))(R^(#)),—C(═NOH)(R^(#)), —CH(═NO(R^(#))), or —CH(═NOH), wherein each R^(#) isindependently as defined herein.

A “hydrazide” group is a radical of the formula:—C(═O)N(R^(#))N(R^(#))₂, —C(═O)NHN(R^(#))₂, —C(═O)N(R^(#))NH(R^(#)),—C(═O)N(R^(#))NH₂, —C(═O)NHNH(R^(#))₂, or —C(═O)NHNH₂, wherein eachR^(#) is independently as defined herein.

A “hydrazine” group is a radical of the formula: —N(R^(#))N(R^(#))₂,—NHN(R^(#))₂, —N(R^(#))NH(R^(#)), —N(R^(#))NH₂, —NHNH(R^(#))₂, or—NHNH₂, wherein each R^(#) is independently as defined herein.

A “hydrazone” group is a radical of the formula:—C(═N—N(R^(#))₂)(R^(#))₂, —C(═N—NH(R^(#)))(R^(#))₂, —C(═N—NH₂)(R^(#))₂,—N(R^(#))(N═C(102), or —NH(N═C(R^(#) ₂), wherein each R^(#) isindependently as defined herein.

An “azide” group is a radical of the formula: —N₃.

An “isocyanate” group is a radical of the formula: —N═C═O.

An “isothiocyanate” group is a radical of the formula: —N═C═S.

A “cyanate” group is a radical of the formula: —OCN.

A “thiocyanate” group is a radical of the formula: —SCN.

A “thioether” group is a radical of the formula; —S(R^(#)), wherein R¹is as defined herein.

A “thiocarbonyl” group is a radical of the formula: —C(═S)(R^(#)),wherein R^(#) is as defined herein.

A “sulfinyl” group is a radical of the formula: —S(═O)(R^(#)), whereinR^(#) is as defined herein.

A “sulfone” group is a radical of the formula: —S(═O)₂(R^(#)), whereinR^(#) is as defined herein.

A “sulfonylamino” group is a radical of the formula: —NHSO₂(R^(#)) or—N(alkyl)SO₂(R^(#)), wherein each alkyl and R^(#) are defined herein.

A “sulfonamide” group is a radical of the formula: —S(═O)₂N(R^(#))₂, or—S(═O)₂NH(R^(#)), or —S(═O)₂NH₂, wherein each R^(#) is independently asdefined herein.

A “phosphonate” group is a radical of the formula: —P(═O)(O(R^(#)))₂,—P(═O)(OH)₂, —OP(═O)(O(R^(#)))(R^(#)), or —OP(═O)(OH)(R^(#)), whereineach R^(#) is independently as defined herein.

A “phosphine” group is a radical of the formula: —P(R^(#))₂, whereineach R^(#) is independently as defined herein.

When the groups described herein, with the exception of alkyl group, aresaid to be “substituted,” they may be substituted with any appropriatesubstituent or substituents. Illustrative examples of substituents arethose found in the exemplary compounds and embodiments disclosed herein,as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl;alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol;thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl;acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone;sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine;hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate;thiocyanate; oxygen (═O); B(OH)₂, O(alkyl)aminocarbonyl; cycloalkyl,which may be monocyclic or fused or non-fused polycyclic (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl,which may be monocyclic or fused or non-fused polycyclic (e.g.,pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl);monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g.,phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl,pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy;aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.

As used herein, the term “Aminopurine Compound” refers to compounds offormula (I) as well as to further embodiments provided herein. In oneembodiment, an “Aminopurine Compound” is a compound set forth inTable 1. The term “Aminopurine Compound” includes pharmaceuticallyacceptable salts, tautomers, isotopologues, and stereoisomers of thecompounds provided herein.

As used herein, the term “pharmaceutically acceptable salt(s)” refers toa salt prepared from a pharmaceutically acceptable non-toxic acid orbase including an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts of thecompounds of formula (I) include, but are not limited to metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methyl-glucamine) and procaine. Suitable non-toxic acids include, butare not limited to, inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonicacid. Specific non-toxic acids include hydrochloric, hydrobromic,maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples ofspecific salts thus include hydrochloride and mesylate salts. Others arewell-known in the art, see for example, Remington's PharmaceuticalSciences, 18^(th) eds., Mack Publishing, Easton Pa. (1990) or Remington:The Science and Practice of Pharmacy, 19^(th) eds., Mack Publishing,Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of an AminopurineCompound that is substantially free of other stereoisomers of thatcompound. For example, a stereomerically pure compound having one chiralcenter will be substantially free of the opposite enantiomer of thecompound. A stereomerically pure compound having two chiral centers willbe substantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, greater than about 90% by weight ofone stereoisomer of the compound and less than about 10% by weight ofthe other stereoisomers of the compound, greater than about 95% byweight of one stereoisomer of the compound and less than about 5% byweight of the other stereoisomers of the compound, or greater than about97% by weight of one stereoisomer of the compound and less than about 3%by weight of the other stereoisomers of the compound. The AminopurineCompounds can have chiral centers and can occur as racemates, individualenantiomers or diastereomers, and mixtures thereof. All such isomericforms are included within the embodiments disclosed herein, includingmixtures thereof.

The use of stereomerically pure forms of such Aminopurine Compounds, aswell as the use of mixtures of those forms, are encompassed by theembodiments disclosed herein. For example, mixtures comprising equal orunequal amounts of the enantiomers of a particular Aminopurine Compoundmay be used in methods and compositions disclosed herein. These isomersmay be asymmetrically synthesized or resolved using standard techniquessuch as chiral columns or chiral resolving agents. See, e.g., Jacques,J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience,New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977);Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY,1962); and Wilen, S. H., Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind., 1972).

It should also be noted the Aminopurine Compounds can include E and Zisomers, or a mixture thereof, and cis and trans isomers or a mixturethereof. In certain embodiments, the Aminopurine Compounds are isolatedas either the E or Z isomer. In other embodiments, the AminopurineCompounds are a mixture of the E and Z isomers.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism and alltautomers of compounds of formula (I) are within the scope of thepresent invention.

It should also be noted the Aminopurine Compounds can contain unnaturalproportions of atomic isotopes at one or more of the atoms. For example,the compounds may be radiolabeled with radioactive isotopes, such as forexample tritium (³H), iodine-125 (¹²⁵I) sulfur-35 (³⁵S), or carbon-14(¹⁴C), or may be isotopically enriched, such as with deuterium (²H),carbon-13 (¹³C), or nitrogen-15 (¹⁵N). As used herein, an “isotopologue”is an isotopically enriched compound. The term “isotopically enriched”refers to an atom having an isotopic composition other than the naturalisotopic composition of that atom. “Isotopically enriched” may alsorefer to a compound containing at least one atom having an isotopiccomposition other than the natural isotopic composition of that atom.The term “isotopic composition” refers to the amount of each isotopepresent for a given atom. Radiolabeled and isotopically encrichedcompounds are useful as therapeutic agents, e.g., cancer andinflammation therapeutic agents, research reagents, e.g., binding assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the Aminopurine Compounds as described herein,whether radioactive or not, are intended to be encompassed within thescope of the embodiments provided herein. In some embodiments, there areprovided isotopologues of the Aminopurine Compounds, for example, theisotopologues are deuterium, carbon-13, or nitrogen-15 enrichedAminopurine Compounds.

“Treating” as used herein, means an alleviation, in whole or in part, ofa disorder, disease or condition, or one or more of the symptomsassociated with a disorder, disease, or condition, or slowing or haltingof further progression or worsening of those symptoms, or alleviating oreradicating the cause(s) of the disorder, disease, or condition itself.In one embodiment, the disorder is melanoma.

“Preventing” as used herein, means a method of delaying and/orprecluding the onset, recurrence or spread, in whole or in part, of adisorder, disease or condition; barring a subject from acquiring adisorder, disease, or condition; or reducing a subject's risk ofacquiring a disorder, disease, or condition. In one embodiment, thedisorder is melanoma, as described herein, or symptoms thereof.

The term “effective amount” in connection with an Aminopurine Compoundmeans an amount capable of treating or preventing a disorder, disease orcondition, or symptoms thereof, disclosed herein. In one embodiment, thedisorder is melanoma.

The term “subject” includes an animal, including, but not limited to, ananimal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail,cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal,in another embodiment a human. In one embodiment, a subject is a humanhaving or at risk for having melanoma, or a symptom thereof.

Aminopurine Compounds

Provided herein are compounds having the following formula (I):

and pharmaceutically acceptable salts, tautomers, stereoisomers,enantiomers, and isotopologues thereof,

wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,or substituted or unsubstituted non-aromatic heterocyclyl;

R² is H or substituted or unsubstituted C₁₋₃ alkyl;

R³ is phenyl, substituted with one or more halogen, optionally furthersubstituted with one or more substitutents independently selected fromsubstituted or unsubstituted C₁₋₃ alkyl, CN, and —OR', wherein each R′is independently substituted or unsubstituted C₁₋₃ alkyl;

provided the compound is not4-[2-[(1-methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide

or4-[8-[(2,4-difluorophenyl)amino]-2-[(trans-4-hydroxycyclohexyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide

In one embodiment, the compound is a compound of formula (II):

In some embodiments or compounds of formula (I), R¹ is substituted orunsubstituted C₁₋₈ alkyl. In some embodiments, R¹ is substituted orunsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, 2-methylpentyl, 3-methylpentyl,isopentyl, or neopentyl. In some embodiments, R¹ is substituted with oneor more substituents independently selected from halogen and OR, whereineach R is independently H or substituted or unsubstituted C₁₋₃ alkyl.For example, R¹ is substituted with one or more substituentsindependently selected from F, OH, and OCH₃. In some embodiments, R¹ isethyl, isopropyl, isobutyl, tert-butyl, CH₂CH₂F, CH₂CHF₂, CH₂CF₃,CH₂CH(CH₃)OH, CH₂CH(CH₃)OCH₃, CH(CH₃)CH₂OH, CH(CH₃)CH₂OCH₃,CH₂C(F₂)CH₂OH, CH₂C(F₂)CH₂OCH₃, CH(CF₃)CH₂OH, CH(CF₃)CH₂OCH₃,CH(CH₂OH)CH₂CH₃, CH(CH₂OCH₃)CH₂CH₃, CH₂C(CH₃)₂CH₂OH, orCH₂C(CH₃)₂CH₂OCH₃. For example, R¹ is isopropyl, isobutyl, tert-butyl,CH₂CF₃, CH₂CH(CH₃)OH, CH(CH₃)CH₂OH, CH(CH₃)CH₂OCH₃, CH₂C(F₂)CH₂OH,CH(CF₃)CH₂OH, CH(CH₂OH)CH₂CH₃, or CH₂C(CH₃)₂CH₂OH.

In one embodiment, R¹ is isopropyl, CH(CH₃)CH₂OH, or CH(CH₂OH)CH₂CH₃. Insome embodiments, R¹ is (S)-2-propan-1-ol:

In some embodiments, R¹ is substituted or unsubstituted cycloalkyl. Insome embodiments, R¹ is substituted or unsubstituted cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In someembodiments, R¹ is substituted with one or more substituentsindependently selected from halogen, OR, SO₂R′, substituted orunsubstituted C₁₋₃ alkyl, and substituted or unsubstituted heterocyclyl,wherein each R is independently H or substituted or unsubstituted C₁₋₃alkyl, and each R′ is independently substituted or unsubstituted C₁₋₃alkyl. In some embodiments, R¹ is substituted with one or moresubstituents independently selected from F, OH, OCH₃, SO₂CH₃, methyl,and substituted or unsubstituted 5-membered heterocyclyl, for example,pyrrolidinedionyl, or oxadiazolyl. In some other embodiments, R¹ iscyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, optionallysubstituted with one or more substituents independently selected from F,OH, OCH₃, SO₂CH₃, methyl, pyrrolidinedionyl, and oxadiazolyl. In someembodiments, R¹ is

wherein

each R^(1a) is independently F, OH, OCH₃, SO₂CH₃, or methyl;

R^(1b) is H or CH₃;

and a is 0-4.

In some embodiments, R¹ is substituted or unsubstituted cycloalkylalkyl.In some embodiments, R¹ is substituted or unsubstituted (C₁₋₃alkyl)-(C₁₋₈ cycloalkyl), for example, R¹ is substituted orunsubstituted CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-cyclopentyl,CH₂-cyclohexyl, or CH₂-cycloheptyl. In some embodiments, R¹ issubstituted with one or more substituents independently selected from(C₁₋₃ alkyl)OR or OR, wherein each R is independently H or substitutedor unsubstituted C₁₋₃ alkyl. For example, R¹ is CH₂-cyclopropyl,CH₂-cyclobutyl, CH₂-cyclopentyl, or CH₂-cyclohexyl, optionallysubstituted with one or more CH₂OH or OH.

In some embodiments, R¹ is substituted or unsubstituted non-aromaticheterocyclyl. In some embodiments, R¹ is substituted or unsubstitutedoxetanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydro-thiopyrandioxide, piperidyl, oxepanyl, or oxaspiroheptyl. Insome embodiments, R¹ is substituted with one or more substituentsindependently selected from halogen, OR, SO₂R⁴, C(═O)R⁵, C(═O)OR⁶,C(═O)NRR⁷, substituted or unsubstituted C₁₋₃ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted or alkylaryl, wherein each R is independently H orsubstituted or unsubstituted C₁₋₃ alkyl; R⁴ is substituted orunsubstituted C₁₋₃ alkyl, or substituted or unsubstituted aryl; R⁵ issubstituted or unsubstituted C₁₋₃ alkyl; R⁶ is substituted orunsubstituted C₁₋₆ alkyl; and R⁷ is substituted or unsubstituted C₁₋₃alkyl, or substituted or unsubstituted aryl. For example, R¹ isoxetanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydro-thiopyrandioxide, piperidyl, oxepanyl, or oxaspiroheptyl,optionally substituted with one or more substituents independentlyselected from F, OH, SO₂CH₃, SO₂-tosyl, C(═O)CH₃, C(═O)OCH₃,C(═O)O-tert-butyl, C(═O)O-isopropyl, C(═O)NHCH₃, C(═O)NH-phenyl, methyl,ethyl, isopropyl, CH₂OH, phenyl, pyridyl, or benzyl. In one embodiment,R¹ is

wherein each R^(1c) is independently F, OH, methyl, or CH₂OH;

and c is 0-3.

In some such embodiments, R^(1c) is F or methyl and c is 1 or 2.

In some embodiments of compounds of formula (I), R² is H. In others, R²is CH₃.

In some embodiments of compounds of formula (I), R³ is ortho-halogensubstituted phenyl. In one embodiment R³ is o-fluoro or o-chlorosubstituted phenyl. In some embodiments, the phenyl is additionally parasubstituted, for example, the phenyl is additionally substituted withp-chloro, p-bromo, p-fluoro, p-CN, p-methyl, p-CF₃, or p-OCH₃. In otherembodiments, R³ is para-halogen substituted phenyl. In some embodiments,R³ is p-fluoro or p-chloro substituted phenyl. In some embodiments, thephenyl is additionally ortho substituted, for example, the phenyl isadditionally substituted with o-chloro, o-fluoro, or o-methyl. In otherembodiments, R³ is para-CN substituted phenyl. In some embodiments, thephenyl is additionally ortho substituted, for example, the phenyl isadditionally substituted with o-chloro, or o-fluoro. In yet otherembodiments, R³ is ortho, ortho-dihalogen substituted phenyl. In oneembodiment R³ is o,o-difluoro or o,o-dichloro substituted phenyl. Insome embodiments, the phenyl is additionally para substituted, forexample, the phenyl is additionally substituted with p-chloro, p-bromo,p-fluoro, p-CN, p-methyl, p-CF₃, or p-OCH₃. In yet other embodiments, R³is ortho, para-dihalogen substituted phenyl. In one embodiment R³ iso,p-difluoro substituted phenyl or o,p-dichloro substituted phenyl. Insome embodiments, the phenyl is additionally ortho substituted, forexample, the phenyl is additionally substituted with o-chloro, o-fluoro,or o-methyl. In still other embodiments, R³ is 2,4,6-trihalogensubstituted phenyl. In one embodiment R³ is 2,4,6-trifluoro substitutedphenyl, 4-chloro-2,6-difluoro subsituted phenyl, or 2,4,6-trichlorosubstituted phenyl. In yet another embodiment, R³ is ortho-halogen,para-CN substituted phenyl. In one embodiment R³ is o-fluoro-p-CNsubstituted phenyl, or o-chloro-para-CN substituted phenyl. In someembodiments, the phenyl is additionally ortho substituted, for example,the phenyl is additionally substituted with o-chloro, or o-fluoro.

In some embodiments of compounds of formula (I), R³ is

wherein

each Hal is independently halogen;

each R⁸ is independently substituted or unsubstituted C₁₋₃ alkyl, CN, orOR′;

each R′ is independently substituted or unsubstituted C₁₋₃ alkyl;

m is 1-3;

and p is 0-2.

In some embodiments, each Hal is independently Cl or F. In others, eachR⁸ is independently CH₃, CF₃, CN, or OCH₃. In yet others, m is 2 or 3.In still others, p is 0 or 1.

In some embodiments of compounds of formula (I), R³ is

and each Hal is independently halogen.

In some embodiments, each Hal is independently F or Cl.

Further embodiments provided herein include combinations of one or moreof the particular embodiments set forth above.

Representative compounds of formula (I) are set forth in Table 1.

Aminopurine Compounds set forth in Table 1 were tested in the Lox-IMVIanti-proliferative assay described herein and were found to haveactivity therein. In one embodiment, the Aminopurine Compound is acompound as described herein, wherein the compound at a concentration of10 μM inhibits melanoma cell proliferation (for example, of a subject'scell, or a cell line, for example Lox-IMVI) by at least about 50% ormore.

Methods for Making Aminopurine Compounds

The Aminopurine Compounds can be made using conventional organicsyntheses and commercially available starting materials. By way ofexample and not limitation, Aminopurine Compounds of formula (I) can beprepared as described in U.S. Pat. No. 7,723,340, and U.S. Pat. No.8,158,635, or as outlined in Scheme 1, shown below, as well as in theexamples set forth herein. It should be noted that one skilled in theart would know how to modify the procedures set forth in theillustrative schemes and examples to arrive at the desired products.

As shown in Scheme 1, compounds of formula (I), wherein R¹, R² and R³are as defined herein, can be prepared starting from an appropriatelyderivatized nitropyrimidine, wherein Hal¹ is Cl, and Hal² is Cl.Treatment of the dihalogenated nitropyrimidine with the appropriate4-aminocyclohexane-1-carboxamide derivative, in the presence of a base,such as, for example, DIEA, TEA, or pyridine, in a solvent, such as forexample, DCM or THF, at reduced temperature (for example, −78° C.),provided incorporation of the cyclohexylamide sidechain. Treatment ofthis product with R¹NH₂, in the presence of a base, such as DIEA, TEA,or pyridine, in a solvent such as DCM, THF, dioxane or DMF, at elevatedtemperature (for example 25-80° C.), resulted in incorporation of the R¹sidechain. Reduction of the nitro moiety, using, for example hydrogen inthe presence of a catalyst such as Pd/C, in a solvent, such as MeOH orethyl acetate, provided the aminopyrimidine derivative. Theaminopyrimidine derivative was treated with R³NCS, in a solvent, such asTHF, DMF, NMP, dioxane, or EtOH, to obtain the (optionally isolated)thiourea derivative, which was cyclized, using for example, EDC or DIC,in a solvent, for example, THF, dioxane, NMP or DMF, optionally atelevated temperature (for example, 40-80° C.), to provide compounds offormula (I).

Alternatively, as shown in Scheme 2, compounds of formula (I), whereinR¹, R² and R³ are as defined herein, and R^(#) is C₁₋₂ alkyl, can beprepared starting from, as before, an appropriately derivatizednitropyrimidine, wherein Hal¹ is Cl, and Hal² is Cl. Treatment of thedihalogenated nitropyrimidine with the appropriate4-aminocyclohexane-1-carboxylate alkyl ester derivative, in the presenceof a base, such as DIEA, TEA or pyridine, in a solvent, such as DCM orTHF, at reduced temperature (for example, −78° C.), providedincorporation of the cyclohexylalkyl ester sidechain. Treatment of thisproduct with R¹NH₂, in the presence of a base, such as DIEA, TEA, orpyridine, in a solvent such as DCM, THF, dioxane or DMF, at elevatedtemperature (for example 25-80° C.), resulted in incorporation of the R¹sidechain. Reduction of the nitro moiety, using, for example hydrogen inthe presence of a catalyst such as Pd/C, in a solvent, such as MeOH orethyl acetate, provided the aminopyrimidine derivative. Theaminopyrimidine derivative was treated with R³NCS, in a solvent, such asTHF, DMF, NMP, dioxane, or EtOH, to obtain the (optionally isolated)thiourea derivative, which was cyclized, using for example, EDC or DIC,in a solvent, for example, THF, NMP, dioxane, or DMF, optionally atelevated temperature (for example, 40° C. to 80° C.), to provide thederivatized diaminopurine derivative. Saponification of the alkyl ester,using a base (such as lithium hydroxide, sodium hydroxide, or potassiumhydroxide), in a solvent (such as aqueous THF, MeOH, or EtOH),optionally at elevated temperature (for example, 40-80° C.), followed byamide formation, via treatment with NH₄Cl, in the presence of a couplingagent (such as, for example, HATU, CDI, HBTU, EDC, optionally incombination with HOBt, or ethyl chloroformate) and a base (such as DIEA,TEA, pyridine, DBU, or NMM), in a solvent, for example, DMF, providedthe compounds of formula (I).

In a third approach, compounds of formula (I), wherein R¹, R² and R³ areas defined herein, and P is a solid support, such as a resin, can beprepared starting from, as before, an appropriately derivatizednitropyrimidine, wherein Hal¹ is Cl, and Hal² is Cl. Treatment of thedihalogenated nitropyrimidine with the appropriate4-aminocyclohexane-1-carboxylate derivative, in the presence of a base,such as DIEA, TEA or pyridine, in a solvent, such as DCM or THF, atreduced temperature (for example, −78° C.), provided incorporation ofthe cyclohexylalkyl carboxylate sidechain. Treatment of this productwith R¹NH₂, in the presence of a base, such as DIEA, TEA, or pyridine,in a solvent such as DCM, THF, dioxane or DMF, at elevated temperature(for example 25-80° C.), resulted in incorporation of the R¹ sidechain.This intermediate was coupled to a solid support, such as a polymericresin (for example, Rink-H resin) using a coupling agent (for example,HATU, CDI, HBTU, EDC, optionally in combination with HOBt, or ethylchloroformate), in a solvent, for example DMF, at elevated temperature,for example 50° C. Treatment of the resin-bound intermediate with areducing agent (such as chromium(II) chloride), in a solvent (such asDMF/MeOH mixture), resulted in reduction of the nitro group. Theresulting amine moiety was reacted with R³NCS, in a solvent, forexample, EtOH, at elevated temperature, for example, 40° C. to 60° C.,providing the thiourea derivative intermediate. This intermediate wascyclized using, for example, EDC or DIC, in a solvent, for example, THF,NMP, dioxane, or DMF, optionally at elevated temperature (for example,40° C. to 80° C.), to provide the resin-bound diaminopurine derivative.Finally, acid treatment (for example, treatment with TFA in a solventsuch as DCM), resulted in cleavage of compounds of formula (I) from theresin.

In one aspect, provided herein are methods for preparing a compound offormula (I):

the methods comprising contacting a compound of formula (Ia)

with EDC or DIC, in a solvent, under conditions suitable to provide acompound of formula (I), wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,or substituted or unsubstituted non-aromatic heterocyclyl;

R² is H or substituted or unsubstituted C₁₋₃ alkyl;

R³ is phenyl, substituted with one or more halogen, optionally furthersubstituted with one or more substitutents selected from substituted orunsubstituted C₁₋₃ alkyl, CN, and —OR′, wherein each R′ is independentlysubstituted or unsubstituted C₁₋₃ alkyl.

In one embodiment, the compound of formula (I) is not4-[2-[(1-methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide,or4-[8-[(2,4-difluorophenyl)amino]-2-[(trans-4-hydroxycyclohexyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide.

In one embodiment, the solvent is THF, dioxane, NMP or DMF. In someembodiments, the contacting is performed at elevated temperature, forexample, from about 40° C. to about 80° C.

In some embodiments, the methods further comprise preparing a compoundof formula (Ia):

the methods comprising contacting a compound of formula (Ib)

with R³NCS, in a solvent, under conditions suitable to provide acompound of formula (Ia).

In one embodiment, the solvent is THF, DMF, NMP, dioxane, or EtOH.

In some embodiments, the methods further comprise preparing a compoundof formula (Ib):

the methods comprising reducing a compound of formula (Ic)

with a reducing agent, in the presence of a catalyst, in a solvent,under conditions suitable to provide a compound of formula (Ib).

In one embodiment, the reducing agents is H₂. In some embodiments, thecatalyst Pd/C. In other embodiments, the solvent is MeOH or ethylacetate.

In some embodiments, the methods further comprise preparing a compoundof formula (Ic):

the methods comprising contacting a compound of formula (Id)

with R¹NH₂, in the presence of a base, in a solvent, under conditionssuitable to provide a compound of formula (Ic), wherein Hal¹ is ahalogen.

In one embodiment, Hal¹ is Cl. In some embodiments, the base is DIEA,TEA, or pyridine. In other embodiments, the solvent is DCM, THF, dioxaneor DMF. In some embodiments, the contacting is performed at elevatedtemperature, for example, from about 25° C. to about 80° C.

In some embodiments, the methods further comprise preparing a compoundof formula (Id):

the methods comprising contacting a compound of formula (Ie)

with

in the presence of a base, in a solvent, under conditions suitable toprovide a compound of formula (Id), wherein Hal² is a halogen.

In one embodiment, Hal² is Cl. In some embodiments, the base is DIEA,TEA, or pyridine. In other embodiments, the solvent is DCM, or THF. Insome embodiments, the contacting is performed at reduced temperature,for example, about −78° C.

In another aspect, provided herein are methods for preparing a compoundof formula (I):

the methods comprising contacting a compound of formula (If)

with NH₄Cl, in the presence of a coupling agent and a base, in asolvent, under conditions suitable to provide a compound of formula (I),wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,or substituted or unsubstituted non-aromatic heterocyclyl;

R² is H or substituted or unsubstituted C₁₋₃ alkyl;

R³ is phenyl, substituted with one or more halogen, optionally furthersubstituted with one or more substitutents selected from substituted orunsubstituted C₁₋₃ alkyl, CN, and —OR′, wherein each R′ is independentlysubstituted or unsubstituted C₁₋₃ alkyl.

In one embodiment, the compound of formula (I) is not4-[2-[(1-methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide,or4-[8-[(2,4-difluorophenyl)amino]-2-[(trans-4-hydroxycyclohexyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide.

In some embodiments, the coupling agent is HATU, CDI, HBTU, EDC,optionally in combination with HOBt, or ethyl chloroformate. Forexample, the coupling agent is HATU. In some embodiments, the base isDIEA, TEA, pyridine, DBU, or NMM. In one embodiment, the solvent is DMF.

In some embodiments, the methods further comprise preparing a compoundof formula (If)

the methods comprising contacting a compound of formula (Ig)

with a base, in a solvent, under conditions suitable to provide acompound of formula (If), wherein R^(#) is C₁₋₂ alkyl.

In one embodiment, the base is lithium hydroxide, sodium hydroxide, orpotassium hydroxide. In some embodiments, the solvent is aqueous THF,MeOH, or EtOH. In some embodiments, the contacting is performed atelevated temperature, for example, from about 40° C. to about 80° C.

In some embodiments, the methods further comprise preparing a compoundof formula (Ig):

the methods comprising contacting a compound of formula (Ih)

with with EDC or DIC, in a solvent, under conditions suitable to providea compound of formula (Ig).

In one embodiment, the solvent is THF, dioxane, NMP or DMF. In someembodiments, the contacting is performed at elevated temperature, forexample, from about 40° C. to about 80° C.

In some embodiments, the methods further comprise preparing a compoundof formula (Ih):

the methods comprising contacting a compound of formula (Ii)

with R³NCS, in a solvent, under conditions suitable to provide acompound of formula (Ih).

In one embodiment, the solvent is THF, DMF, NMP, dioxane, or EtOH.

In some embodiments, the methods further comprise preparing a compoundof formula (Ii):

the methods comprising reducing a compound of formula (Ij)

with a reducing agent, in the presence of a catalyst, in a solvent,under conditions suitable to provide a compound of formula (Ii).

In one embodiment, the reducing agents is H₂. In some embodiments, thecatalyst Pd/C. In other embodiments, the solvent is MeOH or ethylacetate.

In some embodiments, the methods further comprise preparing a compoundof formula (Ij):

the methods comprising contacting a compound of formula (Ik)

with R¹NH₂, in the presence of a base, in a solvent, under conditionssuitable to provide a compound of formula (Ij), wherein Hal¹ is ahalogen.

In one embodiment, Hal¹ is Cl. In some embodiments, the base is DIEA,TEA, or pyridine. In other embodiments, the solvent is DCM, THF, dioxaneor DMF. In some embodiments, the contacting is performed at elevatedtemperature, for example, from about 25° C. to about 80° C.

In some embodiments, the methods further comprise preparing a compoundof formula (Ik):

the methods comprising contacting a compound of formula (Ie)

with

in the presence of a base, in a solvent, under conditions suitable toprovide a compound of formula (Ik), wherein Hal² is a halogen.

In one embodiment, Hal² is Cl. In some embodiments, the base is DIEA,TEA, or pyridine. In other embodiments, the solvent is DCM, or THF. Insome embodiments, the contacting is performed at reduced temperature,for example, about −78° C.

In yet another aspect, provided herein are methods for preparing acompound of formula (I):

the methods comprising contacting a compound of formula (Im)

with an acid, in a solvent, under conditions suitable to provide acompound of formula (I), wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,or substituted or unsubstituted non-aromatic heterocyclyl;

R² is H or substituted or unsubstituted C₁₋₃ alkyl;

R³ is phenyl, substituted with one or more halogen, optionally furthersubstituted with one or more substitutents selected from substituted orunsubstituted C₁₋₃ alkyl, CN, and —OR′, wherein each R′ is independentlysubstituted or unsubstituted C₁₋₃ alkyl; and

P is a resin.

In one embodiment, the compound of formula (I) is not4-[2-[(1-methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide,or4-[8-[(2,4-difluorophenyl)amino]-2-[(trans-4-hydroxycyclohexyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide.

In some embodiments, the acid is TFA. In some embodiments, the solventis DCM. In other embodiments, the resin is Rink resin.

In some embodiments, the methods further comprise preparing a compoundof formula (Im)

the methods comprising contacting a compound of formula (In)

with with EDC or DIC, in a solvent, under conditions suitable to providea compound of formula (Im).

In one embodiment, the solvent is THF, NMP, dioxane, or DMF. In someembodiments, the contacting is performed at elevated temperature, forexample, from about 40° C. to about 80° C.

In some embodiments, the methods further comprise preparing a compoundof formula (In):

the methods comprising contacting a compound of formula (Io)

with with R³NCS, in a solvent, under conditions suitable to provide acompound of formula (In).

In one embodiment, the solvent is EtOH. In some embodiments, thecontacting is performed at elevated temperature, for example, from about40° C. to about 60° C.

In some embodiments, the methods further comprise preparing a compoundof formula (Io):

the methods comprising contacting a compound of formula (Ip)

with a reducing agent, in a solvent, under conditions suitable toprovide a compound of formula (Io).

In one embodiment, the reducing agent is chromium(II) chloride. In oneembodiment, the solvent is DMF, MeOH or mixtures thereof.

In some embodiments, the methods further comprise preparing a compoundof formula (Ip):

the methods comprising contacting a compound of formula (Iq)

with a polymeric resin, in the presence of a coupling agent, in asolvent, under conditions suitable to provide a compound of formula(Ip).

In one embodiment, the coupling agent is HATU, CDI, HBTU, EDC,optionally in combination with HOBt, or ethyl chloroformate. In otherembodiments, the solvent is for example DMF. In some embodiments, thecontacting is performed at elevated temperature, for example about 50°C.

In some embodiments, the methods further comprise preparing a compoundof formula (Iq):

the methods comprising contacting a compound of formula (Ir)

with R¹NH₂, in the presence of a base, in a solvent, under conditionssuitable to provide a compound of formula (Iq), wherein Hal¹ is ahalogen.

In one embodiment, Hal¹ is Cl. In some embodiments, the base is DIEA,TEA, or pyridine. In other embodiments, the solvent is DCM, THF, dioxaneor DMF. In some embodiments, the contacting is performed at elevatedtemperature, for example, from about 25° C. to about 80° C.

In some embodiments, the methods further comprise preparing a compoundof formula (Ir):

the methods comprising contacting a compound of formula (Ie)

with

in the presence of a base, in a solvent, under conditions suitable toprovide a compound of formula (Ir), wherein Hal² is a halogen.

In one embodiment, Hal² is Cl. In some embodiments, the base is DIEA,TEA, or pyridine. In other embodiments, the solvent is DCM, or THF. Insome embodiments, the contacting is performed at reduced temperature,for example, about −78° C.

Methods of Use

The Aminopurine Compounds have utility as pharmaceuticals to treat,prevent or improve conditions in animals or humans. Accordingly,provided herein can be used in all the methods as provided herein.Particularly, the Aminopurine Compounds as provided herein are for usesin the treatment or prevention of melanoma. The methods provided hereincomprise the administration of an effective amount of one or moreAminopurine Compound(s) to a subject in need thereof.

In another aspect provided herein are methods for treating or preventingmelanoma, comprising administering to a subject in need thereof aneffective amount of an Aminopurine Compound, as described herein.Provided herein are the Aminopurine Compounds for use in said methods.

Pharmaceutical Compositions and Routes of Administration

The Aminopurine Compounds can be administered to a subject orally,topically or parenterally in the conventional form of preparations, suchas capsules, microcapsules, tablets, granules, powder, troches, pills,suppositories, injections, suspensions, syrups, patches, creams,lotions, ointments, gels, sprays, solutions and emulsions. Suitableformulations can be prepared by methods commonly employed usingconventional, organic or inorganic additives, such as an excipient(e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose,talc, calcium phosphate or calcium carbonate), a binder (e.g.,cellulose, methylcellulose, hydroxymethylcellulose,polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic,polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch,carboxymethylcellulose, hydroxypropylstarch, low substitutedhydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calciumcitrate), a lubricant (e.g., magnesium stearate, light anhydrous silicicacid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citricacid, menthol, glycine or orange powder), a preservative (e.g, sodiumbenzoate, sodium bisulfate, methylparaben or propylparaben), astabilizer (e.g., citric acid, sodium citrate or acetic acid), asuspending agent (e.g., methylcellulose, polyvinyl pyrroliclone oraluminum stearate), a dispersing agent (e.g.,hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax(e.g., cocoa butter, white petrolatum or polyethylene glycol). Theeffective amount of the Aminopurine Compounds in the pharmaceuticalcomposition may be at a level that will exercise the desired effect; forexample, about 0.005 mg/kg of a subject's body weight to about 10 mg/kgof a subject's body weight in unit dosage for both oral and parenteraladministration.

The dose of an Aminopurine Compound to be administered to a subject israther widely variable and can be subject to the judgment of ahealth-care practitioner. In general, the Aminopurine Compounds can beadministered one to four times a day in a dose of about 0.005 mg/kg of asubject's body weight to about 10 mg/kg of a subject's body weight in asubject, but the above dosage may be properly varied depending on theage, body weight and medical condition of the subject and the type ofadministration. In one embodiment, the dose is about 0.01 mg/kg of asubject's body weight to about 5 mg/kg of a subject's body weight, about0.05 mg/kg of a subject's body weight to about 1 mg/kg of a subject'sbody weight, about 0.1 mg/kg of a subject's body weight to about 0.75mg/kg of a subject's body weight or about 0.25 mg/kg of a subject's bodyweight to about 0.5 mg/kg of a subject's body weight. In one embodiment,one dose is given per day. In any given case, the amount of theAminopurine Compound administered will depend on such factors as thesolubility of the active component, the formulation used and the routeof administration. In one embodiment, application of a topicalconcentration provides intracellular exposures or concentrations ofabout 0.01-10 μM.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration ofabout 0.375 mg/day to about 750 mg/day, about 0.75 mg/day to about 375mg/day, about 3.75 mg/day to about 75 mg/day, about 7.5 mg/day to about55 mg/day or about 18 mg/day to about 37 mg/day of an AminopurineCompound to a subject in need thereof.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration ofabout 1 mg/day to about 1200 mg/day, about 10 mg/day to about 1200mg/day, about 100 mg/day to about 1200 mg/day, about 400 mg/day to about1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day toabout 800 mg/day or about 600 mg/day to about 800 mg/day of anAminopurine Compound to a subject in need thereof. In a particularembodiment, the methods disclosed herein comprise the administration of400 mg/day, 600 mg/day or 800 mg/day of an Aminopurine Compound to asubject in need thereof.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 1 mg and 200 mg, about 35 mg and about 1400 mg,about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about500 mg and about 1000 mg of an Aminopurine Compound.

In a particular embodiment, provided herein are unit dosage formulationscomprising about 100 mg or 400 mg of an Aminopurine Compound.

In another embodiment, provided herein are unit dosage formulations thatcomprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg,100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg,560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of an Aminopurine Compound.

An Aminopurine Compound can be administered once, twice, three, four ormore times daily. In a particular embodiment, doses of 600 mg or lessare administered as a once daily dose and doses of more than 600 mg areadministered twice daily in an amount equal to one half of the totaldaily dose.

An Aminopurine Compound can be administered orally for reasons ofconvenience. In one embodiment, when administered orally, an AminopurineCompound is administered with a meal and water. In another embodiment,the Aminopurine Compound is dispersed in water or juice (e.g., applejuice or orange juice) and administered orally as a suspension.

The Aminopurine Compound can also be administered intradermally,intramuscularly, intraperitoneally, percutaneously, intravenously,subcutaneously, intranasally, epidurally, sublingually, intracerebrally,intravaginally, transdermally, rectally, mucosally, by inhalation, ortopically to the ears, nose, eyes, or skin. The mode of administrationis left to the discretion of the health-care practitioner, and candepend in-part upon the site of the medical condition.

In one embodiment, provided herein are capsules containing anAminopurine Compound without an additional carrier, excipient orvehicle.

In another embodiment, provided herein are compositions comprising aneffective amount of an Aminopurine Compound and a pharmaceuticallyacceptable carrier or vehicle, wherein a pharmaceutically acceptablecarrier or vehicle can comprise an excipient, diluent, or a mixturethereof. In one embodiment, the composition is a pharmaceuticalcomposition.

The compositions can be in the form of tablets, chewable tablets,capsules, solutions, parenteral solutions, troches, suppositories andsuspensions and the like. Compositions can be formulated to contain adaily dose, or a convenient fraction of a daily dose, in a dosage unit,which may be a single tablet or capsule or convenient volume of aliquid. In one embodiment, the solutions are prepared from water-solublesalts, such as the hydrochloride salt. In general, all of thecompositions are prepared according to known methods in pharmaceuticalchemistry. Capsules can be prepared by mixing an Aminopurine Compoundwith a suitable carrier or diluent and filling the proper amount of themixture in capsules. The usual carriers and diluents include, but arenot limited to, inert powdered substances such as starch of manydifferent kinds, powdered cellulose, especially crystalline andmicrocrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders.

Tablets can be prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant might be necessary in a tablet formulation to prevent thetablet and punches from sticking in the dye. The lubricant can be chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils. Tablet disintegrators aresubstances that swell when wetted to break up the tablet and release thecompound. They include starches, clays, celluloses, algins and gums.More particularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose,for example, can be used as well as sodium lauryl sulfate. Tablets canbe coated with sugar as a flavor and sealant, or with film-formingprotecting agents to modify the dissolution properties of the tablet.The compositions can also be formulated as chewable tablets, forexample, by using substances such as mannitol in the formulation.

When it is desired to administer an Aminopurine Compound as asuppository, typical bases can be used. Cocoa butter is a traditionalsuppository base, which can be modified by addition of waxes to raiseits melting point slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use.

The effect of the Aminopurine Compound can be delayed or prolonged byproper formulation. For example, a slowly soluble pellet of theAminopurine Compound can be prepared and incorporated in a tablet orcapsule, or as a slow-release implantable device. The technique alsoincludes making pellets of several different dissolution rates andfilling capsules with a mixture of the pellets. Tablets or capsules canbe coated with a film that resists dissolution for a predictable periodof time. Even the parenteral preparations can be made long-acting, bydissolving or suspending the Aminopurine Compound in oily or emulsifiedvehicles that allow it to disperse slowly in the serum.

EXAMPLES

The following Examples are presented by way of illustration, notlimitation. Compounds are named using the automatic name generating toolprovided in Chemdraw Ultra 9.0 (Cambridgesoft), which generatessystematic names for chemical structures, with support for theCahn-Ingold-Prelog rules for stereochemistry. One skilled in the art canmodify the procedures set forth in the illustrative examples to arriveat the desired products.

Abbreviations used:

Cbz Carboxybenzyl CDI Carbonyldiimidazole DAST Diethylaminosulfurtrifluoride DBU 1 8-Diazabicyclo 5.4.0 undec-7-ene DCM DichloromethaneDEA Diethylamine DIC Diisopropylcarbodiimide DIEA DiisopropylethylamineDMA N,N-Dimethylacetamide DME 1,2-Dimethoxyethane DMFN,N-Dimethylformamide DMSO Dimethylsulfoxide DPPA Diphenylphosphorylazide EDC Ethyl-(N′,N′-dimethylamino)propylcarbodiimide hydrochlorideESI Electrospray ionization EtOH Ethanol HATUO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HMPA Hexamethylphosphoramide HOBt1-Hydroxybenzotriazole HPLC High performance liquid chromatography HTRFHomogeneous time resolved fluorescence LCMS Liquid chromatography massspectrometry mCPBA Meta-chloroperoxybenzoic acid MeOH Methanol MS Massspectrometry MTBE tert-Butyl Methyl ether NMM N-Methylmorpholine NMPN-methylpyrrolidone NMR Nuclear magnetic resonance pTSAp-Toluenesulfonic acid SFC Supercritical fluid chromatography TBTUO-Benzotriazol-1-yl-N,N,N′,N′-tetra- methyluronium tetrafluoroboratet-BuOH Tert-butanol TEA Triethylamine TFA Trifluoracetic acid THFTetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilane

Compound Synthesis Example 1(1s,4s)-4-(8-((4-Chloro-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

cis-(4-Carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester.cis-4-tert-Butoxycarbonylamino-cyclohexanecarboxylic acid (1 equiv.) andTEA (1.1 equiv.) were dissolved in 0.3 M THF and the mixture was cooledto 0° C. Ethyl chloroformate (1.1 equiv.) was added drop-wise. Afterstirring at 0° C. for 30 min, NH₃ in THF was added. The mixture wasallowed to stir at −78° C. for 2 h. The mixture was diluted with water,and the solvent was evaporated until only water remained. The resultingprecipitate was collected by filtration and dried under vacuum to givecis (4-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (45%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.10 (brs, 1H), 6.69 (brs,2H), 3.41 (brs, 1H), 2.10 (m, 1H), 1.72 (m, 2H), 1.53 (m, 2H), 1.42 (m,4H), 1.36 (s, 9H).

cis-4-Amino-cyclohexanecarboxylic acid amide hydrochloride. To asolution of cis-(4-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester(1 equiv.) in 1/1 DCM /TFA. The mixture was stirred for 1 h. Thesolvents were evaporated under reduced pressure. To the resultingresidue was added 2M HCl/ether to give a white solid. The solvent wasevaporated. The resulting solid was treated with ether and filtered togive cis-4-amino-cyclohexanecarboxylic acid amide hydrochloride (100%)as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.08 (brs, 3H), 7.28 (s, 1H), 6.78 (s,1H), 3.06 (m, 1H), 2.22 (m, 1H), 1.86 (m, 2.H), 1.66 (m, 4H), 1.48 (m,2H).

(1s,4s)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamide.(1s,4s)-4-Aminocyclohexanecarboxamide hydrochloride (0.56 mol) and2,4-dichloro-5-nitropyrimidine (1 equiv.) were dissolved in DCM (0.16M). The mixture was cooled to −78° C. An addition funnel was chargedwith DIEA (3 equiv.) and DCM (1.0M). The DIEA solution was addeddropwise via an addition funnel. After the addition was complete, thereaction was stirred for an additional 2 h at −78° C. The reaction wasmonitored by LCMS. Once the reaction was completed, the reaction mixturewas partitioned between DCM and water, the organic layer was separatedand dried over anhydrous sodium sulfate. The mixture was filtered, thenthe filtrate was concentrated and washed with a mixture of petroleumether and ethyl acetate (1:1) to give(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamide(65%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.01 (s, 1H),8.51 (d, J=7.6 Hz, 1H), 7.23 (s, 1H), 6.75 (s,1H), 4.26 (s, 1H), 2.24(s, 1H), 1.60-1.83 (m,8H).

5-Chloro-1,3-difluoro-2-isothiocyanatobenzene. To a solution of4-chloro-2,6-difluoroaniline (1 equiv.) in anhydrous DCM (0.24 M) wasadded DIEA (2.5 equiv) in one portion. After stirring for 30 min at roomtemperature, the mixture was cooled to 0° C. and thiophosgene (1.8equiv) was added dropwise over 1 h at this temperature. TLC (petroleumether) showed that the reaction was finished. The mixture wasconcentrated, the residue was purified by silica gel columnchromatography to give 5-chloro-1,3-difluoro-2-isothiocyanatobenzene(97%) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.02 (d,J=7.2 Hz, 2H).

(1s,4s)-4-((5-Nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide.(1s,4s)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) and tetrahydro-2H-pyran-4-amine hydrochloride (1 equiv.) weredissolved in THF (0.5 M) and DIEA (2.5 equiv.) was added. The reactionwas stirred at 70° C. for 3 h, diluted with water, and filtered to give(1s,4s)-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(98% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.84 (s,1H); 8.52 (d, J=7.1Hz, 1H); 8.39 (d, J=7.1 Hz, 1H); 7.23 (s, 1H); 6.74(s, 1H); 4.24 (s, 1H); 3.87 (m, 3H); 3.58 (s, 1H); 3.10 (s, 1H); 2.22(m, 2H); 1.61 (m, 13H); 1.25 (m, 5H).

(1s,4s)-4-((5-Amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide.To a round-bottom flask was added(1s,4s)-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl) amino)pyrimidin-4-yl)amino)cyclohexane-carboxamide (1 equiv.) and Pd-C (0.1equiv., 10% Pd by wt.) in MeOH (0.15 M) to give a black suspension. Thesuspension was stirred under 1 atm of H₂ overnight. The reaction wascomplete as shown by LCMS. The reaction mixture was filtered, and washedwith additional MeOH. The filtrate was concentrated in vacuo to give(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide (87%). MS (ESI) m/z=335.1 [M+1]⁺.

(1s,4s)-4-((5-(3-(4-Chloro-2,6-difluorophenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide.In a three-necked flask was added(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) and 5-chloro-1,3-difluoro-2-isothiocyanatobenzene (1 equiv.)in THF/DMF (3/1, 0.5 M) to give a purple suspension. The reaction wasstirred at room temperature for 72 h. LCMS showed that a small amount ofstarting material remained. The reacton was partitioned between DCM andwater. The organic layer was separated, dried over Na₂SO₄, filtered andevaporated in vacuo to afford(1s,4s)-4-((5-(3-(4-chloro-2,6-difluorophenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide (79%yield). MS (ESI) m/z 540=[M+1]⁺.

(1s,4s)-4-(8-((4-Chloro-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide. In a round-bottom flask wasadded(1s,4s)-4-((5-(3-(4-chloro-2,6-difluorophenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) and EDC (2 equiv.) in THF (0.2 M) to give an off-whitesuspension. The suspension was heated to 60° C. for 1 h. Standardwork-up and purification methods afforded(1s,4s)-4-(8-((4-chloro-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide (57% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm: 8.37 (br. s., 1H) 8.02 (br. s., 1H) 7.46 (d, J=6.31Hz, 2H) 7.26 (br. s., 1H) 6.72 (br. s., 1H) 4.52 (br. s., 1H) 4.08 (br.s., 1H) 3.86 (dt, J=11.74, 3.74 Hz, 2H) 3.64 (t, J=10.56 Hz, 2H)2.59-2.72 (m, 2H) 2.21 (d, J=12.93 Hz, 2H) 1.93 (d, J=9.77 Hz, 2H) 1.68(d, J=10.72 Hz, 2H) 1.55-1.65 (m, 2H) 1.44-1.55 (m, 2H). MS (ESI)m/z=506.2 [M+1]⁺.

Example 2(1s,4s)-4-(2-((Tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

(1s,4s)-4-(2-((Tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.A mixture of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) and 1,3,5-trichloro-2-isothiocyanatobenzene (1 equiv.) wasstirred at room temperature for 2 h. EDC (2 equiv.) in THF (0.17 M) wasadded and the reaction was heated to 60° C. and stirred for 1 h. Thereaction was cooled, and the organic solvents were fully concentrated.The resulting residue was diluted with water, stirred for 30 min, andfiltered. Standard work-up and purification methods afforded(1s,4s)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(79% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.11 (br. s., 1H) 7.69(br. s., 2H) 7.23 (br. s., 1H) 6.71 (br. s., 1H) 4.47 (br. s., 1H) 4.05(br. s., H) 3.86 (dt, J=11.59, 3.66 Hz, 2H) 3.61 (d, J=11.03 Hz, 2H)2.59-2.74 (m, 2H) 2.20 (d, J=13.24 Hz, 2H) 1.90 (d, J=10.40 Hz, 2H) 1.69(br. s., 2H) 1.41-1.64 (m, 4H). MS (ESI) m/z=540.2 [M+H]⁺.

Example 3(1s,4s)-4-(8-((2-Chloro-4,5-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide

1-Chloro-4,5-difluoro-2-isothiocyanatobenzene. To a mixture of2-chloro-4,5-difluoroaniline (1 equiv.) and sodium hydroxide (3 equiv.)in DCM (0.24 M) and water (0.24 M) was added dropwise thiophosgene (3equiv.) at 0° C. The reaction mixture was stirred at 25° C. overnight.TLC showed the reaction was complete. The organic phase was separatedand dried over MgSO₄, then concentrated to give1-chloro-4,5-difluoro-2-isothiocyanatobenzene (53%) as a white solid.

(1s,4s)-4-(8-((2-Chloro-4,5-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) in DMF (0.24 M) was added1-chloro-4,5-difluoro-2-isothiocyanatobenzene (1.1 equiv.) in oneportion. The mixture was stirred at room temperature for 2 h. EDC (2.5equiv.) was added to the reaction solution. The resulting mixture wasstirred at room temperature overnight. Standard work-up and purificationmethods afforded(1s,4s)-4-(8-((2-chloro-4,5-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(35%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.21-8.21 (m, 1H), 8.02-7.54 (m, 2H),7.24 (s, 1H), 6.74 (s, 1H), 6.53 (d, J=6.0 Hz, 1H), 4.34-4.20 (m, 1H),3.85-3.83 (m, 3H), 3.60-3.45 (m, 2H), 2.73-2.51 (m, 2H), 2.48-2.39 (m,1H), 2.23 (d, J=13.3 Hz, 2H), 1.91-1.79 (m, 2H), 1.74-1.37 (m, 6H). MS(ESI) m/z=506.1 [M+1]⁺.

Example 4(1s,4s)-4-(8-((2-Chloro-4-fluoro-6-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

2-Chloro-4-fluoro-6-methylaniline. To a mixture of4-fluoro-2-methylaniline (1 equiv.) in acetonitrile (0.4 M) was addedNCS (1 equiv.) at 90° C. The mixture was stirred at 90° C. for 1 h. Themixture was concentrated to a residue, the residue was purified viasilica gel chromatography to give 2-chloro-4-fluoro-6-methylaniline(24%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.87 (dd, J=8.4,2.8 Hz, 1H), 7.73 (dd, J=8.8, 2.8 Hz 2.8 Hz, 1H), 2.17 (s, 3H).

1-Chloro-5-fluoro-2-isothiocyanato-3-methylbenzene. To a mixture of2-chloro-4-fluoro-6-methylaniline 2 (0.3 g, 1.9 mmol) in DCM/H₂O (1/2,0.15 M) was added NaOH (21 equiv.) and SCCl₂ (5 equiv.) at 0° C. Afteraddition, the mixture was allowed to warm to room temperature andstirred for 16 h. The mixture was filtered, and the filtrate wasextracted with DCM. The combined organic layers were dried over Na₂SO₄,and concentrated to a residue. The residue was purified by silicachromatograhpy to give1-chloro-5-fluoro-2-isothiocyanato-3-methylbenzene (52%) as a yellowoil.

cis-4-(8-((2-Chloro-4-fluoro-6-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein) in DMF (0.12 M) was added1-chloro-5-fluoro-2-isothiocyanato-3-methylbenzene (1 equiv.). Thereaction mixture was stirred at room temperature for 1 h, and DIC (2equiv.) was added. The mixture was stirred at room temperature for 16 h.Standard work-up and purification methods providedcis-4-(8-((2-chloro-4-fluoro-6-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(50%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.93 (s, 1H), 7.21 (t, J=7.2Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 4.34 (s, 1H), 4.07-3.96 (m, 3H),3.71-3.66 (s, 2H), 2.93-2.90 (m, 2H), 2.67 (s, 1H), 2.35-231 (m, 5H),2.04-2.01 (m, 2H), 1.82-1.80 (m, 4H), 1.58-1.51 (m, 2H). MS (ESI)m/z=502.2 [M+1]⁺.

Example 5(1s,4s)-4-(8-((2,3-Difluoro-4-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

2,3-Difluoro-4-methylaniline. To a mixture of2-chloro-6-fluoro-3-methylbenzoic acid (1 equiv.) in THF (0.45 M) wasadded DPPA (1.07 equiv.) and TEA (3 equiv.) at 25° C. The mixture wasstirred at 25° C. for 2 h, then the mixture was heated to reflux for 2h. Water was added to the reaction and the mixture was refluxed for 1 h.The mixture was concentrated to a residue, which was purified by silicagel chromatography to give 2-chloro-6-fluoro-3-methylaniline (46%) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.83 (dd, J=8.4, 10.3 Hz,1H), 6.56 (dd, J=5.8, 8.3 Hz, 1H), 4.08 (br.s., 1H), 2.31 (s, 1H).

2,3-Difluoro-1-isothiocyanato-4-methylbenzene. To a mixture of2-chloro-6-fluoro-3-methylaniline (1 equiv.) in DCM/water (1/2, 0.1 M)was added NaOH (6 equiv.) and SCCl₂ (3 equiv.) at 0° C. After addition,the mixture was allowed to warm to room temperature and was stirred for16 h. The mixture was filtered, the filtrate was extracted with DCM, andthe combined organic layers were dried over Na₂SO₄, and concentrated toa residue. The residue was purified by silica gel chromatography to give2,3-difluoro-1-isothiocyanato-4-methylbenzene (63%) as a yellow oil. ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.09 (dd, J=5.7, 8.6 Hz, 1H), 7.01-6.93 (m,1H), 2.36 (s, 3H).

(1s,4s)-4-(84(2,3-Difluoro-4-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein) in DMF (0.12 M) was added2,3-difluoro-1-isothiocyanato-4-methylbenzene (1 equiv.). The reactionmixture was stirred at 25° C. for 1 h. DIC (2 equiv.) was added to themixture and stirring at 25° C. was continued for 16 h. Standard work-upand purification methods providedcis-4-(8-((2-chloro-6-fluoro-3-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(42%). ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.96 (s, 1H), 7.31-6.92 (m, 2H),4.42 (s, 1H), 4.12-3.91 (m, 3H), 3.68 (t, J=11.3 Hz, 2H), 2.89 (d,J=11.7 Hz, 2H), 2.65 (s, 1H), 2.45-2.23 (m, 5H), 2.09-1.97 (m, 2H),1.92-1.68 (m, 4H), 1.62-1.47 (m, 2H). MS (ESI) m/z=486.3 [M+1]⁺.

Example 6(1s,4s)-4-(8-((2-Chloro-3-fluoro-4-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

2-Chloro-3-fluoro-4-methylaniline. To a cooled (0° C.) solution of3-fluoro-4-methylaniline (1 equiv.) in DMF (1.6 M) was added NCS (1equiv.). After the addition was finished, the reaction was allowed towarm to room temperature and stirred for 18 h. The reaction was dilutedwith ethyl acetate, washed with saturated Na₂SO₃, dried over Na₂SO₄,filtered and concentrated. The resulting residue was purified via silicagel column chromatography providing 2-chloro-3-fluoro-4-methylaniline(8%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.87 (t, J=8.1Hz, 1H), 6.49 (dd, J=1.2, 8.2 Hz, 1H), 4.02 (s, 2H), 2.20 (d, J=1.8 Hz,3H).

2-Chloro-3-fluoro-1-isothiocyanato-4-methylbenzene. To a cooled solutionof 2-chloro-3-fluoro-4-methylaniline (1 equiv.) in DCM/H₂O (1/1, 0.3 M)was added NaOH (3 equiv.), followed by dropwise SCCl₂ (3 equiv.) for 10min. After the addition, the mixture was stirred for 60 min at roomtemperature. The reaction was diluted with petroleum ether, and filteredthrough a pad of silica gel. The filtrate was concentrated to afford2-chloro-3-fluoro-1-isothiocyanato-4-methylbenzene (48%) as a yellowoil.

(1s,4s)-4-(8-((2-Chloro-3-fluoro-4-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein) in anhydrous DMF (0.15 M) wasadded 2-chloro-3-fluoro-1-isothiocyanato-4-methylbenzene (3 equiv.), andthe mixture was stirred at room temperature for 90 min. DIC (6 equiv.)was added and the mixture was stirred at room temperature. Standardwork-up and purification methods affordedcis-4-(8-((2-chloro-3-fluoro-4-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(40%). ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 8.07 (s, 1H), 7.34-7.12 (m, 2H),4.37 (s, 1H), 4.11-3.92 (m, 3H), 3.71 (t, J=11.0 Hz, 2H), 2.89 (d,J=11.0 Hz, 2H), 2.67 (s, 1H), 2.47-2.17 (m, 5H), 2.04 (d, J=11.5 Hz,2H), 1.89-1.71 (m, 4H), 1.64-1.47 (m, 2H). MS (ESI) m/z=502.2 [M+1]⁺.

Example 7(1s,4s)-4-(8-((4-Chloro-2,5-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

4-Chloro-2,5-difluoroaniline. To a mixture of1-chloro-2,5-difluoro-4-nitrobenzene (1 equiv.) in acetic acid (0.5 M)was added Fe (5 equiv.), which was heated to reflux at 110° C. for 3 h.The mixture was filtered, the filtrate was concentrated to give thecrude product, which was purified by silica gel chromatography to give4-chloro-2,5-difluoroaniline (80%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ ppm: 7.08-6.99 (m, 1H), 6.65 (dd, J=7.8, 10.7 Hz, 1H).

1-Chloro-2,5-difluoro-4-isothiocyanatobenzene. To a mixture of4-chloro-2,5-difluoroaniline (1.0 g, 6.1 mmol) in DCM/water (0.1 M, 1/2)added NaOH (6 equiv.) and SCCl₂ (3 equiv.) at 0° C. After addition, themixture was allowed to warm to room temperature and stirred for 16 h.The mixture was filtered, and the filtrate was extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, and concentrated to aresidue. The residue was purified by silica gel chromatography to give1-chloro-2,5-difluoro-4-isothiocyanatobenzene (48%) as a yellow oil. ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.26-7.22 (m, 1H), 7.00 (dd, J=6.7, 8.5 Hz,1H).

(1s,4s)-4-(8-((4-Chloro-2,5-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-carboxamide(1 equiv.) (prepared as described herein) in DMF (0.37 M) was added1-chloro-2,5-difluoro-4-isothiocyanatobenzene (1 equiv.). The reactionmixture was stirred at 25° C. for 1 h. DIC (1 equiv.) was added and themixture was stirred at 25° C. for 16 h. Standard work-up andpurification methods afforded(1s,4s)-4-(8-((4-chloro-2,5-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(32%). ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 8.16 (s, 1H), 7.75 (s, 1H), 7.38(s, 1H), 4.34 (s, 1H), 4.11-3.84 (m, 3H), 3.69 (t, J=11.2 Hz, 2H), 2.87(d, J=11.7 Hz, 2H), 2.65 (s, 1H), 2.31 (d, J=12.9 Hz, 2H), 2.02 (d,J=12.8 Hz, 2H), 1.75 (s, 4H), 1.64-1.45 (m, 2H). MS (ESI) m/z=506.2[M+1]⁺.

Example 8(1s,4s)-4-(84(4-Chloro-2,3-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

4-Chloro-2,3-difluoroaniline. To a mixture of1-chloro-2,3-difluoro-4-nitrobenzene (1 equiv.) in acetic acid (0.5 M)was added Fe (5 equiv.). After addition, the mixture was refluxed for 3h. The mixture was filtered, the filtrate was concentrated to give aresidue. The residue was purified by silica gel chromatography to give4-chloro-2,3-difluoroaniline (41%) as a yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 7.05-6.98 (m, 1H), 6.62-6.53 (m, 1H), 5.67 (br.s, 2H).

1-Chloro-2,3-difluoro-4-isothiocyanatobenzene. To a mixture of4-chloro-2,3-difluoroaniline (1 equiv.) in DCM/water (0.3 M, 1/27) wasadded NaOH (3 equiv.) and SCCl₂ (3 equiv.) at 0° C. After addition, themixture was allowed to warm to 25° C. and was stirred for 2 h. Themixture was filtered, and the filtrate was extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, and concentrated to givea residue. The residue was purified by silica gel chromatography to give1-chloro-2,3-difluoro-4-isothiocyanatobenzene (68%) as a yellow oil. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 7.54-7.47 (m, 1H), 7.41-7.34 (m, 1H).

(1s,4s)-4-(84(4-Chloro-2,3-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein) in DMF (0.3 M) was added1-chloro-2,3-difluoro-4-isothiocyanatobenzene 2 (1.2 equiv.). Thereaction mixture was stirred at 30° C. for 1 h. DIC (2 equiv.) wasadded, and the mixture was stirred at 30° C. for 16 h. Standard work-upand purification methods afforded(1s,4s)-4-(8-((4-chloro-2,3-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(26%). ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 8.11 (s, 1H), 7.46-7.36 (m, 1H),7.33-7.23 (m, 1H), 4.42-4.29 (m, 1H), 4.11-3.94 (m, 3H), 3.77-3.65 (m,2H), 3.00-2.79 (m, 2H), 2.70-2.64 (m, 1H), 2.39-2.28 (m, 2H), 2.09-1.98(m, 2H), 1.85-1.71 (m, 4H), 1.64-1.52 (m, 2H). MS (ESI) m/z=506.2[M+1]⁺.

Example 9(1s,4s)-4-(8-((2,4-Difluoro-6-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

2,4-Difluoro-6-((methylthio)methyl)aniline. To a mixture of2,4-difluoroaniline (1 equiv.) in DCM (0.5 M) was added Me₂S (1 equiv.),NCS (1 equiv.) and TEA (1 equiv.) at −15° C. After addition, the mixturewas allowed to warm to room temperature. The mixture was heated toreflux for 16 h. The mixture was concentrated in vacuo. The residue waspurified by silica gel chromatography to afford2,4-difluoro-6-((methylthio)methyl)aniline (40%) as a brown oil. ¹H NMR(400 MHz, CDCl₃) δ ppm: 6.75 (ddd, J=2.9, 8.3, 10.8 Hz, 1H), 6.62 (td,J=2.2, 8.8 Hz, 1H), 3.67 (s, 2H), 2.01 (s, 3H).

2,4-Difluoro-6-methylaniline. To a mixture of2,4-difluoro-6-((methylthio)methyl)aniline (1 equiv.) in EtOH (0.32 M)was added Raney Ni under N₂. The mixture was stirred under H₂ (50 psi)for 16 h. The mixture was filtered, and the filtrate was concentrated togive 2,4-difluoro-6-methylaniline 3 (0.8 g, yield:89%) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ ppm: 6.74-6.53 (m, 2H), 3.63-3.34 (m, 2H),2.19 (s, 3H).

1,5-Difluoro-2-isothiocyanato-3-methylbenzene. To a mixture of2,4-difluoro-6-methylaniline (1 equiv.) in DCM/water (1/2, 0.2 M) wasadded NaOH (6 equiv.) and SCCl₂ (3 equiv.) at 0° C. After addition, themixture was allowed to warm to room temperature and stirred for 16 h.The mixture was filtered, and the filtrate was extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, and concentrated to aresidue. The residue was purified by silica gel chromatography toprovide 1,5-difluoro-2-isothiocyanato-3-methylbenzene (48%) as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.80-6.72 (m, 2H), 2.39 (s, 3H).

(1s,4s)-4-(8-((2,4-Difluoro-6-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein) in DMF (0.12 M) was added1,5-difluoro-2-isothiocyanato-3-methylbenzene (1 equiv.). The reactionmixture was stirred at 25° C. for 1 h. To the reaction was added DIC (2equiv.), and the mixture was stirred at 25° C. for 16 h. Standardwork-up and purification methods afforded(1s,4s)-4-(8-((2,4-Difluoro-6-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(54%). ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 7.93 (s, 1H), 6.98-6.79 (m, 2H),4.39 (t, J=12.0 Hz, 1H), 4.09-3.90 (m, 3H), 3.67 (dt, J=1.9, 11.5 Hz,2H), 2.99-2.79 (m, 2H), 2.66 (s, 1H), 2.37-2.17 (m, 5H), 2.06-1.95 (m,2H), 1.87-1.71 (m, 4H), 1.63-1.47 (m, 2H). MS (ESI) m/z=486.3 [M+1]⁺.

Example 10(1s,4s)-4-(8-((2-Chloro-6-fluoro-3-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

2-Chloro-6-fluoro-3-methylaniline. To a mixture of2-chloro-6-fluoro-3-methylbenzoic acid (1 equiv.) in THF (0.3 M) wasadded DPPA (1.07 equiv.), and TEA (3 equiv.) at 25° C. The mixture wasstirred at 25° C. for 2 h, then the mixture was heated to reflux for 2h. Water was added and the reaction was refluxed for 1 h. The mixturewas concentrated to a residue, which was purified via silica gelchromatography to give 2-chloro-6-fluoro-3-methylaniline (46%) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.83 (dd, J=8.4, 10.3 Hz,1H), 6.56 (dd, J=5.8, 8.3 Hz, 1H), 4.08 (br.s., 1H), 2.31 (s, 1H).

2-Chloro-4-fluoro-3-isothiocyanato-1-methylbenzene. To a mixture of2-chloro-6-fluoro-3-methylaniline (1 equiv.) in DCM/water (1/2, 0.1 M)was added NaOH (6 equiv.) and SCCl₂ (3 equiv.) at 0° C. After addition,the mixture was allowed to warm to room temperature and stirred for 16h. The mixture was filtered. The filtrate was extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, and concentrated to aresidue. The residue was purified via silica gel chromatography(petroleum ether) to give2-chloro-4-fluoro-3-isothiocyanato-1-methylbenzene (63%) as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.09 (dd, J=5.7, 8.6 Hz, 1H),7.01-6.93 (m, 1H), 2.36 (s, 3H).

(1s,4s)-4-(8-((2-chloro-6-fluoro-3-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein) in DMF (0.1 M) was added2-chloro-4-fluoro-3-isothiocyanato-1-methylbenzene (1 equiv.). Thereaction mixture was stirred at 25° C. for 1 h. To the reaction mixturewas added DIC (2 equiv.). The mixture was stirred at 25° C. for 16 h.Standard work-up and purification methods providedcis-4-(8-((2-chloro-6-fluoro-3-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(42%). ¹H NMR (400 MHz, MeOH-d₄) δ ppm: 7.96 (s, 1H), 7.31-6.92 (m, 2H),4.42 (s, 1H), 4.12-3.91 (m, 3H), 3.68 (t, J=11.3 Hz, 2H), 2.89 (d,J=11.7 Hz, 2H), 2.65 (s, 1H), 2.45-2.23 (m, 5H), 2.09-1.97 (m, 2H),1.92-1.68 (m, 4H), 1.62-1.47 (m, 2H). MS (ESI) m/z=502.1 [M+1]⁺.

Example 11(1s,4s)-4-(8-((3,4-Dichloro-2-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide

1,2-Dichloro-3-fluoro-4-isothiocyanatobenzene. A solution of sodiumhydroxide (3 equiv.) in water (0.5 M) was added to a solution of3,4-dichloro-2-fluoroaniline (1 equiv.) in DCM (1 M). The mixture wascooled to 0° C. and thiophosgene (3 equiv.) was added dropwise viasyringe. The reaction mixture was allowed to warm to room temperaturefor 16 h. The mixture was extracted with DCM , the combined organiclayers were dried over sodium sulfate and concentrated under vacuum. Theresidue was purified by column chromatography to afford1,2-dichloro-3-fluoro-4-isothiocyanatobenzene (79%) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.24 (dd, J=8.8, 2.0 Hz, 1H), 7.06 (t, J=8.2Hz, 1H).

(1s,4s)-4-(8-((3,4-Dichloro-2-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.A solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-carboxamide(1 equiv.) (prepared as described herein) and1,2-dichloro-3-fluoro-4-isothiocyanatobenzene (1.2 equiv.) in DMF (0.5M) was stirred at room temperature for 2 h. LCMS showed that theintermediate thiourea was formed. Then EDC (2.5 equiv.) was added andthe reaction was stirred for another 16 h. Standard work-up andpurification methods afforded(1s,4s)-4-(8-((3,4-dichloro-2-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(31%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.01 (brs, 1H), 7.47 (s,1H), 7.35 (dd, J=8.8, 2.0 Hz, 1H), 4.39-4.35 (m, 1H), 4.04-3.96 (m, 3H),3.72-3.66 (m, 2H), 2.89-2.85 (m, 2H), 2.65 (s, 1H), 2.32 (d, J=12.4 Hz,2H), 2.02 (d, J=10.8 Hz, 2H), 1.78-1.55 (m, 4H), 1.16-1.12 (m, 2H). MS(ESI) m/z=522.2 [M+1]⁺.

Example 12(1s,4s)-4-((5-(3-(2-Chloro-4-cyano-6-fluorophenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide

4-Amino-3-chloro-5-fluorobenzonitrile. A mixture of4-amino-3-fluorobenzonitrile (1 equiv.) and N-chlorosuccinimide (1.5equiv.) in acetonitrile (0.24 M) was stirred at 85° C. for 5 h. Thesolvent was removed by concentration and the residue was partitionedbetween ethyl acetate and 5% NaOH. The organic phase was washed with 5%NaOH and brine. Then the organic phase was dried over MgSO₄ and dried invacuum to afford 4-amino-3-chloro-5-fluorobenzonitrile (88%) as a beigesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.41 (t, J=6 Hz, 1H), 7.24 (dd,J=1.8, 10.2 Hz, 1H), 4.66 (s, 2H).

3-Chloro-5-fluoro-4-isothiocyanatobenzonitrile. To a mixture of4-amino-3-chloro-5-fluorobenzonitrile (1 equiv.) and DIEA (3.5 equiv.)in DCM (1 M) was added thiophosgene (3.5 equiv.) at 0° C. . The reactionwas stirred at room temperature overnight. The solvent was removed andthe residue was purified by preparative TLC to give3-chloro-5-fluoro-4-isothiocyanatobenzonitrile (34%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ ppm: 7.55 (t, J=1.6 Hz, 1H), 7.40 (dd, J=1.7,8.5 Hz, 1H).

(1s,4s)-4-((5-(3-(2-Chloro-4-cyano-6-fluorophenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide.A mixture of 3-chloro-5-fluoro-4-isothiocyanatobenzonitrile (1 equiv.)and(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-carboxamide(1 equiv.) (prepared as described herein) in DMF was stirred at roomtemperature overnight. The solvent was removed and the residue waspurified by preparative TLC to give(1s,4s)-4-((5-(3-(2-chloro-4-cyano-6-fluorophenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(33%) as a yellow solid. MS (ESI) m/z=547.2 [M+1]⁺.

(1s,4s)-4-(84(2-Chloro-4-cyano-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of(1s,4s)-4-((5-(3-(2-chloro-4-cyano-6-fluorophenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) in DME was added EDC (2.5 equiv.) in one portion. Theresulting mixture was stirred at room temperature overnight. Standardwork-up and purification methods afforded(1s,4s)-4-(842-chloro-4-cyano-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(43%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.71 (s, 1H), 7.56 (d, J=9.7Hz, 1H), 4.54 (t, J=12.2 Hz, 1H), 4.06-3.95 (m, 3H), 3.69 (t, J=11.3 Hz,2H), 2.92-2.78 (m, 2H), 2.68-2.63 (m, 1H), 2.33 (d, J=14.2 Hz, 2H), 2.03(d, J=13.7 Hz, 2H), 1.83-1.70 (m, 4H), 1.64-1.52 (m, 2H). MS (ESI) m/z531.2 [M+1]⁺.

Example 13(1s,4s)-4-(84(4-Cyano-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

3,5-Difluoro-4-isothiocyanatobenzonitrile. To a cooled (0° C.) solutionof 4-amino-3,5-difluorobenzonitrile (1 equiv.) in anhydrous DCM (0.2 M)was added DIEA (2.5 equiv.) in one portion. Then sulfonyl chloride (1.5equiv.) was added dropwise over 20 min. After the addition, the reactionmixture was stirred for about 3 h at 0° C. The solvent was evaporated togive a brown solid, which was purified by column chromatography to give3,5-difluoro-4-isothiocyanatobenzonitrile (67%) as a light yellow solid.

(1s,4s)-4-(8-((4-Cyano-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(prepared as described herein) in anhydrous DMF (3.0 mL) was added3,5-difluoro-4-isothiocyanatobenzonitrile (1 equiv.). After theaddition, the reaction mixture was stirred for 1 h at room temperature.EDC (2.5 equiv.) was added in one portion. The reaction mixture wasstirred for 16 h at room temperature. Standard work-up and purificationmethods afforded(1s,4s)-4-(8-((4-cyano-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(9%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.14 (s, 1H), 7.70-7.41 (m,2H), 4.55 (s, 1H), 3.99 (d, J=11.67 Hz, 3H), 3.70 (t, J=10.79 Hz, 2H),2.86 (s, 2H), 2.66 (s, 1H), 2.33 (d, J=12.55 Hz, 2H), 2.02 (d, J=11.54Hz, 2H), 1.76 (s, 4H), 1.67-1.47 (m, 2H). MS (ESI) m/z=497.2 [M+1]⁺.

Example 14(1s,4s)-4-(8-((3-Cyano-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

3-Cyano-2,6-difluorobenzoic acid. To a cooled (0° C.) solution ofdiisopropylamine (1.15 equiv.) in anhydrous THF was added n-BuLi (1.15equiv.) dropwise over a period of 10 min. After the addition, thesolution was stirred for about 30 mins at 0° C. The mixture was cooledto −78° C. and stirred for about 30 mins. A solution of2,4-difluorobenzonitrile (1 equiv.) in THF was added dropwise over aperiod of 20 min. The reaction solution was stirred for 10 mins at −78°C. and CO₂ was bubbled into the mixture via a syringe for 15 min. Thereaction was stirred at −78° C. for 2 h. HCl (6 M) was added into thereaction to pH=3-4. The aqueous phase was extracted with DCM/MeOH. Thecombined organic layers were washed with saturated sodium chloridesolution, dried over sodium sulfate, filtered and concentrated in vacuumto give a white residue, which was purified by column chromatography onsilica gel to give to 3-cyano-2,6-difluorobenzoic acid (53%) as a whitesolid.

tert-Butyl (3-cyano-2,6-difluorophenyl)carbamate. To a solution of3-cyano-2,6-difluorobenzoic acid (1 equiv.) in 1:4 t-BuOH/dioxane wasadded DPPA (1.1 equiv.), di-t-butyl dicarbonate (1.2 equiv.) andtriethanolamine (3.5 equiv.). After the addition, the reaction washeated to 100° C., and stirred for about 6 h. The solvent wasconcentrated to give a white residue, and water was added to theresidue. The aqueous phase was extracted with ethyl acetate. Thecombined organic layers were washed with saturated sodium chloridesolution, dried over sodium sulfate, filtered and concentrated in vacuumto give a white residue, which was purified by column chromatography onsilica gel to give to tert-butyl (3-cyano-2,6-difluorophenyl)carbamate(38%) as a white solid.

3-Amino-2,4-difluorobenzonitrile. tert-Butyl(3-cyano-2,6-difluorophenyl)carbamate (1 equiv.) was dissolved in 4 MHCl/1,4-Dioxane (0.2 M). The reaction mixture was stirred for 4 h atroom temperature. The solvent was concentrated to give3-amino-2,4-difluorobenzonitrile (93%) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm: 7.19-7.09 (m, 1H), 7.09-6.99 (m, 1H), 5.85 (s, 2H).

2,4-Difluoro-3-isothiocyanatobenzonitrile. To a cooled (0° C.) solutionof 3-amino-2,4-difluorobenzonitrile (1 equiv.) in anhydrous DCM (1.0 mL)was added DIEA (4 equiv.) in one portion. Sulfonyl chloride (5 equiv.)was added dropwise over 10 min. After the addition, the reaction mixturewas stirred for about 0.5 h at 0° C. The reaction was warmed to roomtemperature and stirred for 3 h. The solvent was evaporated to give abrown solid, which was purified by column chromatography on silica gelto give 2,4-difluoro-3-isothiocyanatobenzonitrile (31%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.60-7.45 (m, 1H), 7.13 (td,J=8.72, 1.64 Hz, 1H).

(1s,4s)-4-(84(3-Cyano-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein) in anhydrous DMF was added2,4-difluoro-3-isothiocyanatobenzonitrile (1.1 equiv.). After theaddition, the reaction mixture was stirred for 2 h at room temperature.DIC (1.1 equiv.) was added in one portion. The reaction mixture wasstirred for 16 h at room temperature. Standard work-up and purificationmethods providedcis-4-(8-((3-cyano-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(15%).

¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.00 (s, 1H), 7.79-7.56 (m, 1H),7.33-7.06 (m, 1H), 4.49 (s, 1H), 4.12-3.91 (m, 3H), 3.70 (t, J=10.98 Hz,2H), 3.00-2.75 (m, 2H), 2.67 (s, 1H), 2.34 (d, J=13.68 Hz, 2H), 2.03 (d,J=11.04 Hz, 2H), 1.89-1.68 (m, 4H), 1.46-1.65 (m, 2H). MS (ESI) m/z497.3 =[M+1]⁺.

Example 15(1s,4s)-4-(8-((2-Chloro-6-fluoro-4-(trifluoromethyl)phenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

2-Chloro-6-fluoro-4-(trifluoromethyl)aniline. To a mixture of2-fluoro-4-(trifluoromethyl)aniline (1 equiv.) in acetonitrile (10 mL)was added N-chlorosuccinimide (1.15 equiv.) at 90° C. The reactionmixture was stirred at 90° C. for 5 h. The mixture was concentrated togive a residue. The residue was purified via silica gel chromatographyto give the desired product 2-chloro-6-fluoro-4-(trifluoromethyl)aniline(50%). ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.36 (s, 1H), 7.20 (d, J=10.4 Hz,1H), 4.41 (s, 2H).

1-Chloro-3-fluoro-2-isothiocyanato-5-(trifluoromethyl)benzene. To asolution of 2-chloro-6-fluoro-4-(trifluoromethyl)aniline (1 equiv.) inDCM (5 mL) was added DIEA (3 equiv.) and thiocarbonyl dichloride (3equiv.). After addition, the mixture was heated to 50° C. and stirredfor 2 h. TLC (petroleum ether/ethyl acetate=50:1) showed2-chloro-6-fluoro-4-(trifluoromethyl)aniline was consumed completely.The mixture was concentrated and purified with silica gel chromatographyto give the desired product1-chloro-3-fluoro-2-isothiocyanato-5-(trifluoromethyl)benzene (67%) as ayellow solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 7.51 (s, 1H), 7.35 (d, J=8.8 Hz, 1H).

(1s,4s)-4-(8-((2-Chloro-6-fluoro-4-(trifluoromethyl)phenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(prepared as described herein) (1 equiv.), in DMF was added1-chloro-3-fluoro-2-isothiocyanato-5-(trifluoromethyl)benzene (1equiv.). The reaction mixture was stirred at 30° C. for 2 h. To thereaction mixture was added EDC (2 equiv.), the mixture was stirred at30° C. for 16 h. Standard work-up and purification methods afforded(1s,4s)-4-(8-((2-chloro-6-fluoro-4-(trifluoromethyl)phenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(32%).

¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.63-7.53 (m, 2H), 7.48-7.39 (m,1H), 4.60-4.47 (m, 1H), 4.07-3.90 (m, 3H), 3.75-3.62 (m, 2H), 2.97-2.75(m, 2H), 2.66-2.59 (m, 1H), 2.37-2.27 (m, 2H), 2.04-1.95 (m, 2H),1.88-1.68 (m, 4H), 1.62-1.47 (m, 2H). MS (ESI) m/z=556.2 [M+1]⁺.

Example 16(1s,4s)-4-(84(3-Chloro-2-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

(1s,4s)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxylicacid. 2,4-Dichloro-5-nitropyrimidine (1 equiv.) and(1s,4s)-4-aminocyclohexanecarboxylic acid (1 equiv.) were suspended inTHF and cooled to −78° C. DIEA (3 equiv.) was added drop wise and thereaction was stirred at −78° C. for 45 min. The cooling bath was removedand the reaction was stirred at room temperature overnight. The solventwas removed under reduced pressure to give the desired product(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxylicacid (84%), which was filtered and used without further purification. MS(ESI) m/z 301.2 [M+1]⁺.

(1s,4s)-4-((5-Nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylicacid.(1s,4s)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxylicacid (1 equiv.) and tetrahydro-2H-pyran-4-amine hydrochloride (1 equiv.)were suspended in THF followed by the addition of DIEA (4 equiv.). Thereaction was stirred at 50° C. overnight. The solvent was reduced invacuo to give the desired product(1s,4s)-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxylicacid (69%). The product was used without further purification. MS (ESI)m/z 366.4 [M+1]⁺.

Resinbound-(1s,4s)-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide.(1s,4s)-4-((5-Nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxylicacid (1 equiv.) was dissolved in DMF, followed by the addition of Rink-Hresin (1 equiv.) and HOBt (1.5 equiv.). The reaction mixture was stirredovernight followed by the addition of EDC (2.3 equiv.), and the reactionmixture was heated at 50° C. for 1 h. The resin was washed with threeportions of MeOH, three portions of DCM, three portions of MeOH, and twoportions of ether. The resin was taken forward into the next step. MS(ESI) m/z 484.2 [M+1]⁺.

Resinbound-(1s,4s)-4-((5-(3-(3-chloro-2-methylphenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide.Resin bound(1s,4s)-N-methyl-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) was treated with DMF:MeOH (3:1) ratio followed by theaddition of chromium(II) chloride (3 equiv.) The reaction mixture wasstirred overnight at room temperature followed by the addition of1-chloro-3-isothiocyanato-2-methylbenzene (5 equiv.). The resin waswashed with three portions of MeOH followed by three portions of DCM,then rinsed with EtOH. The resin once washed was taken into the nextstep. MS (ESI) m/z 519.2 [M+1]⁺.

(1s,4s)-4-(8-((3-Chloro-2-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.Resin bound(1s,4s)-4-((5-(3-(3-chloro-2-methylphenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) was suspended in EtOH followed by the addition of EDC (5equiv.). The reaction mixture was heated to 50° C. for 3 h. The resinwas washed with three portions of MeOH followed by three portions ofDCM, then MeOH/DCM alternating the wash three times each. The resin wasthen transferred to a vial and 50% DCM/TFA was used to cleave thecompound from the resin. The mixture was left to stir for 30 min,filtered, the resin was rinsed with DCM and the filtrate wasconcentrated under reduced pressure to afford(1s,4s)-4-(8-((3-chloro-2-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamideas the TFA salt. Standard workup and purification methods afforded(1s,4s)-4-(8-((3-chloro-2-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(7%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.31 (s, 1H), 8.10 (s, 1H), 7.56(d, J=7.81 Hz, 1H), 7.32 (d, J=1.17 Hz, 1H), 7.10-7.28 (m, 2H), 6.76(br. s., 1H), 6.45 (d, J=7.81 Hz, 1H), 4.30 (br. s., 1H), 3.78-3.94 (m,3H), 3.53 (t, J=10.94 Hz, 2H), 2.57-2.76 (m, 2H), 2.13-2.36 (m, 5H),1.85 (d, J=12.50 Hz, 2H), 1.34-1.71 (m, 7H). MS (ESI) m/z=484.2 [M+1]⁺.

Example 17(1s,4s)-4-(8-((2-Chloro-4-cyanophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

3-Chloro-4-isothiocyanatobenzonitrile. To a cooled (0° C.) solution of4-amino-3-chlorobenzonitrile (1 equiv.) in anhydrous DCM (0.65 M) wasadded DIEA (3 equiv.) in one portion. Then CSCl₂ (3 equiv.) was addeddropwise over 20 min. After the addition, the reaction mixture wasstirred for about 2 h at 0° C. The solvent was evaporated to give abrown solid, which was purified by column chromatography on silica gel)to give 3-chloro-4-isothiocyanatobenzonitrile (61%) as a light yellowsolid.

(1s,4s)-4-(8-((2-Chloro-4-cyanophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein) in anhydrous DMF (0.3 M) wasadded 3-chloro-4-isothiocyanatobenzonitrile (1 equiv.). After theaddition, the reaction mixture was stirred for 1 h at room temperature.DIC (2 equiv.) was added in one portion. The reaction mixture wasstirred for 16 h at room temperature. Standard work-up and purificationmethods afforded(1s,4s)-4-(8-((2-chloro-4-cyanophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(14%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.29 (s, 1H), 7.88 (s, 1H),7.76-7.52 (m, 2H), 4.32 (s, 1H), 4.10-3.96 (m, 4H), 3.76-3.66 (m, 2H),2.87 (d, J=10.67 Hz, 2H), 2.66 (s, 1H), 2.33 (d, J=13.55 Hz, 2H), 2.03(s, 2H), 1.82-1.70 (m, 4H), 1.60 (d, J=11.80 Hz, 2H). MS (ESI) m/z=495.2[M+1]⁺.

Example 18(1s,4s)-4-(84(2,3-Difluoro-4-(trifluoromethoxy)phenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

2,3-Difluoro-4-methoxyaniline. To a mixture of2,3-difluoro-1-methoxy-4-nitrobenzene 1 (1 equiv.) in EtOH (0.5 M) wasadded SnCl₂ (5 equiv.). Then HCl (25 mL) was added and the reaction wasstirred at room temperature for 16 h. Ethyl acetate and H₂O were added,and the aqueous layer was extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄, and filtered, then the filtratewas concentrated in vacuo to give 2,3-difluoro-4-methoxyaniline (90%) asa brown solid.

2,3-Difluoro-1-isothiocyanato-4-methoxybenzene. To a solution of2,3-difluoro-4-methoxyaniline (1 equiv.) in DCM (0.8 M) was added DIEA(2.5 equiv.) at 0° C., then SCCl₂ (5 equiv.) was added drop-wise at 0°C. The reaction mixture was stirred at room temperature for 2 h. Theorganic solvent was condensed in vacuo and purified via silica gel togive 2,3-difluoro-1-isothiocyanato-4-methoxybenzene (94%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.42-7.27 (m, 1H), 7.08 (dt,J=2.1, 8.9 Hz, 1H), 3.99-3.83 (m, 3H).

(1s,4s)-4-(8-((2,3-Difluoro-4-(trifluoromethoxy)phenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of 2,3-difluoro-1-isothiocyanato-4-methoxybenzene (1equiv.) in DMF (0.5 M) was added (1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein). The mixture was stirred atroom temperature for 1 h. To the mixture obtained in the previous stepwas added DIC (2 equiv.). The mixture was stirred at room temperaturefor 12 h. Standard work-up and purification methods afforded (1s,4s)-4-(8-((2,3-difluoro-4-methoxyphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(5%). ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.33 (s, 1H), 7.76 (dt, J=2.5, 8.8Hz, 1H), 7.37 (s, 1H), 6.96-6.75 (m, 1H), 5.61-5.39 (m, 2H), 4.81-4.55(m, 2H), 4.19-3.98 (m, 3H), 3.92 (s, 3H), 3.67-3.54 (m, 2H), 2.85-2.66(m, 2H), 2.63 (brs., 1H), 2.22 (d, J=15.4 Hz, 2H), 2.14-2.03 (m, 2H),1.94-1.72 (m, 4H), 1.58-1.46 (m, 2H). MS (ESI) m/z=502.3 [M+1]⁺.

Example 19(1s,4s)-4-(8-((4-Fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

Methyl (1s,4s)-4-aminocyclohexane-1-carboxylate hydrochloride. To asolution of cis-4-aminocyclohexanecarboxylic acid (1 equiv.) in drymethanol (0.5 M), was added dropwise sulfurous dichloride (4 equiv.).The reaction was stirred at room temperature for 2 h. The solvent wasremoved in vacuum to give methyl(1s,4s)-4-aminocyclohexane-1-carboxylate hydrochloride (96%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃-d₄) δ ppm: 8.34 (br. s., 3H), 3.80-3.66(m, 3H), 3.32 (br. s., 1H), 2.58 (br. s., 1H), 2.31-1.50 (m, 8H).

Methyl(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxylate.2,4-Dichloro-5-nitropyrimidine (1 equiv.) and methyl(1s,4s)-4-aminocyclohexane-1-carboxylate hydrochloride (1 equiv.) weredissolved in THF (0.5 M) and cooled to −78° C. DIEA (2.5 equiv.) wasadded dropwise and the reaction was stirred at −78° C. for 45 min. Thecooling bath was removed and the reaction was stirred at roomtemperature for 4 h. The solvent was removed in vacuo to give methyl(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxylate(95%) as a yellow solid, which was used directly into the next stepwithout further purification. MS (ESI) m/z=315.1 [M+1]⁺.

Methyl(1s,4s)-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate.To a mixture of methyl(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxylate(1 equiv.) and tetrahydro-2H-pyran-4-amine (1.2 equiv.) in THF (0.3 M)was added DIEA (3 equiv.). The mixture was stirred at 70° C. overnight.Water and ethyl acetate were added to the mixture and the layers wereseparated. The aqueous layer was extracted with ethyl acetate. Thecombined organic layers were dried over Na₂SO₄ and concentrated in vacuoto give methyl(1s,4s)-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate(60%) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 9.06-8.90 (m, 1H),8.64-8.35 (m, 1H), 5.70-5.30 (m, 1H), 4.2 (m, 1H), 4.07-3.95 (m, 3H),3.72 (m, 3H), 3.60-3.46 (m, 2H), 2.60-2.47 (m, 1H), 2.04-1.92 (m, 4H),1.89-1.69 (m, 6H), 1.65-1.55 (m, 2H). MS (ESI) m/z=380.2 [M+1]⁺.

Methyl(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate.To methyl(1s,4s)-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate(1 equiv.) in MeOH (0.3 M) was added Pd/C (0.1 equiv, 10% Pd by wt.)under nitrogen atmosphere. The mixture was hydrogenated overnight underH₂ (1 atm). The reaction was filtered over Celite and washed with MeOH.The filtrate was concentrated in vacuo to give methyl(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate,which was used into the next step without further purification. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 7.23 (s, 1H), 5.78 (d, J=7.2 Hz, 1H), 5.54 (d,J=8.0 Hz, 1H), 4.01-3.90 (m, 1H), 3.89-3.77 (m, 4H), 3.75-3.65 (m, 1H),3.63 (s, 3H), 3.34-3.28 (m, 2H), 2.61-2.53 (m, 1H), 2.00-1.90 (m, 2H),1.79 (dd, J=1.9, 12.4 Hz, 2H), 1.75-1.67 (m, 2H), 1.62-1.35 (m, 6H).

Methyl(1s,4s)-4-(8-((4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylate.To methyl(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate(1 equiv.) in DMF (0.2 M) was added 1-fluoro-4-isothiocyanatobenzene (1equiv.). The reaction was stirred at room temperature for 2 h. Thereaction solution was used directly in the next step without furtherpurification. To the reaction solution from above was added DIC (1equiv.). The reaction was stirred at 50° C. overnight. Water and ethylacetate were added to the solution and the layers were separated. Theaqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water, then dried over Na₂SO₄ and concentratedin vacuo. The residue was washed with ethyl acetate to give methyl(1s,4s)-4-(8-((4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylate(64%) as white solid. MS (ESI) m/z=469.3 [M+1]⁺.

(1s,4s)-4-(8-((4-Fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylicacid. A mixture of methyl(1s,4s)-4-(8-((4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylate(1 equiv.), LiOH (1 equiv.) and THF/H₂O (4/1, 0.1 M) was stirred at 70°C. overnight. Water was added to the residue, the pH of the mixture wasadjusted to 6 with 1N HCl, and the solution was filtered to give(1s,4s)-4-(8-((4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylicacid (88%) as white solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.01 (s,1H), 7.67-7.58 (m, 2H), 7.13 (t, J=8.8 Hz, 2H), 4.46-4.35 (m, 1H),4.18-4.06 (m, 1H), 4.03-3.94 (m, 2H), 3.77 (dt, J=11.2, 1.8 Hz, 2H),2.89-2.73 (m, 3H), 2.41 (d, J=13.7 Hz, 2H), 2.08-2.03 (m, 2H), 1.88-1.74(m, 4H), 1.71-1.54 (m, 2H).

(1s,4s)-4-(8-((4-Fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-(8-((4-Fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylicacid (1 equiv.) in DMF (0.2 M) was added NH₄Cl (3.3 equiv.), DIEA (4equiv.) and HATU (1.2 equiv.). The reaction was stirred at roomtemperature overnight. Standard work-up and purification methodsprovided(1s,4s)-4-(8-((4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylicacid (36%).

¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.95 (s, 1H), 7.76-7.71 (m, 2H),7.20-7.13 (m, 2H), 4.51 (tt, J=12.0, 4.0 Hz, 1H), 4.27-4.14 (m, 1H),4.01 (td, J=11.2, 3.6 Hz, 2H), 3.76 (t, J=11.2 2H), 2.95-2.82 (m, 2H),2.74-2.68 (m, 1H), 2.32 (d, J=13.6 Hz, 2H), 2.05 (dd, J=12.8, 2.4 Hz,2H), 1.89-1.78 (m, 4H), 1.73-1.61 (m, 2H). MS (ESI) m/z=454.3 [M+H]⁺.

Example 20(1s,4s)-4-(8-((2,6-Dichloro-4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

Methyl(1s,4s)-4-((5-(3-(2,6-dichloro-4-fluorophenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate.To a solution of (1s,4s)-methyl4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxylate(1 equiv.) (prepared as described herein) in DMF (0.3 M) was added1,3-dichloro-5-fluoro-2-isothiocyanatobenzene (1 equiv.). The reactionwas stirred at 25° C. for 2 h. The mixture was used directly in nextstep without further purification. MS (ESI) m/z=571.1 [M+H]⁺.

(1s,4s)-Methyl4-(8-((2,6-dichloro-4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxylate.To the solution from above was added DIC (2 equiv.). The mixture wasstirred at 40° C. for 16 h. The mixture was diluted with brine andfiltered. The filter cake was crystallized with ethyl acetate to give(1s,4s)-methyl4-(8-((2,6-dichloro-4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxylate(82%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.44-8.13 (m, 1H), 7.17 (d,J=7.6 Hz, 2H), 4.94-4.79 (m, 1H), 4.59-4.44 (m, 1H), 4.12-3.95 (m, 3H),3.74 (s, 3H), 3.68-3.57 (m, 2H), 2.83-2.75 (m, 1H), 2.75-2.60 (m, 2H),2.39-2.28 (m, 2H), 2.11-2.01 (m, 2H), 1.81-1.61 (m, 4H), 1.60-1.46 (m,2H).

(1s,4s)-4-(8-((2,6-Dichloro-4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxylicacid. To a mixture of (1s,4s)-methyl4-(8-((2,6-dichloro-4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxylate(1 equiv.) in THF/water (5/1, 0.12 M) was added LiOH (5 equiv.). Thereaction was stirred at 60° C. for 16 h. Water was added to the mixtureand the pH was adjusted to 6 with 1N HCl, then the mixture wasconcentrated to give the crude product, which was used directly in nextstep without further purification. MS (ESI) m/z=523.1 [M+H]⁺.

(1s,4s)-4-(8-((2,6-Dichloro-4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of(1s,4s)-4-(8-((2,6-dichloro-4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxylicacid (1 equiv.) in DMF (0.2 M) was added DIEA (2 equiv.), HATU (1.2equiv.) and NH₄Cl (2 equiv.). The reaction was stirred at roomtemperature for 2 h. Standard work-up and purification methods afforded(1s,4s)-4-(8-((2,6-dichloro-4-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(30%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.04-7.87 (m, 1H), 7.48-7.18(m, 2H), 4.53-4.34 (m, 1H), 4.08-3.91 (m, 3H), 3.74-3.61 (m, 2H),2.97-2.77 (m, 2H), 2.70-2.62 (m, 1H), 2.38-2.26 (m, 2H), 2.06-1.96 (m,2H), 1.88-1.71 (m, 4H), 1.63-1.48 (m, 2H). MS (ESI) m/z=522.2 [M+H]⁺.

Example 21(1s,4s)-4-(8-((2,6-Difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

cis-Ethyl4-(8-((2,6-Difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexanecarboxylate.To a solution of ethyl(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(prepared as described herein) (1 equiv.) in anhydrous DMF (0.36 M) wasadded 1,3-difluoro-2-isothiocyanatobenzene (1 equiv.). The mixture wasstirred at room temperature for 90 min. DIC (2 equiv.) was added andstirring was continued at room temperature. The reaction was dilutedwith water, and extracted with ethyl acetate. The combined extracts wereevaporated. The residue was purified by column chromatgraphy to affordcis-ethyl4-(8-((2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexanecarboxylate(80%) as a yellow solid. MS (ESI) m/z=515.3 [M+H]⁺.

(1s,4s)-4-(8-((2,6-Difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylicacid. To cis-ethyl4-(8-((2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexanecarboxylate(1 equiv.) in MeOH/water (0.1 M, 3/1) was added KOH (7 equiv.). Thereaction was refluxed for 72 h. The reaction was concentrated, dilutedwith water, and extracted with ethyl acetate. The aqueous layer wasacidified with 6 M HCl to pH=3-5, and extracted with ethyl acetate. Thecombined extracts were evaporated to afford(1s,4s)-4-(8-((2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylicacid (67%) as a yellow solid, which was used directly into the next stepwithout further purification.

To a solution of(1s,4s)-4-(8-((2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylicacid (1 equiv.) in DMF (0.3 M) were added HATU (2 equiv.), TEA (2equiv.) and NH₄Cl (2 equiv.). The reaction was stirred at roomtemperature overnight. Standard work-up and purification methodsafforded(1s,4s)-4-(8-((2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide(88%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.00 (br. s., 1H), 7.45-6.92(m, 3H), 4.37 (br. s., 1H), 4.07-3.93 (m, 3H), 3.72 (t, J=10.7 Hz, 2H),2.79 (d, J=12.0 Hz, 2H), 2.41 (d, J=13.1 Hz, 2H), 2.04 (d, J=13.7 Hz,2H), 1.84 (d, J=11.0 Hz, 2H), 1.65-1.53 (m, 2H), 1.46 (dt, J=3.1, 13.8Hz, 2H), 1.26 (s, 3H). MS (ESI) m/z=486.2 [M+H]⁺.

Example 22(1s,4s)-1-Methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate. To a solution of ethyl4-oxocyclohexanecarboxylate (1 equiv.) in DCM (0.6 M) were addedethane-1,2-diol (2 equiv.), triethoxymethane (2 equiv.) and pTSA (0.05equiv.). The reaction was stirred at room temperature overnight. Thereaction was concentrated in vacuum. The resulting residue was dilutedwith petroleum/ethyl acetate, filtered through a pad of silica gel. Thefiltrate was concentrated to give ethyl1,4-dioxaspiro[4.5]decane-8-carboxylate (100%). ¹H NMR (400 MHz, CDCl₃)δ ppm: 4.11 (q, J=7.2 Hz, 2H), 3.93 (s, 4H), 2.37-2.26 (m, 1H),1.98-1.87 (m, 2H), 1.85-1.71 (m, 4H), 1.59-1.48 (m, 2H), 1.22 (t, J=7.2Hz, 3H).

Ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate. To a cooled (0°C.) solution of DIA (1.2 equiv.) in anhydrous THF (1 M) was added n-BuLi(1.6 equiv.) dropwise for 20 min. The mixture was stirred for 30 min at0° C. and then cooled to −78° C. A solution of ethyl1,4-dioxaspiro[4.5]decane-8-carboxylate (1 equiv.) in THF (1 M) wasadded dropwise for 30 min, followed by iodomethane (3 equiv.). Thereaction mixture was stirred overnight at room temperature. The reactionwas diluted with brine and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over Na₂SO₄ and filtered.The filtrate was concentrated to give ethyl8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate 3 (100%). ¹H NMR (400MHz, CDCl₃) δ ppm: 4.16 (q, J=7.1 Hz, 2H), 3.95 (s, 4H), 2.19-2.11 (m,2H), 1.72-1.57 (m, 4H), 1.57-1.45 (m, 2H), 1.30-1.24 (m, 3H), 1.20 (s,3H).

Ethyl 1-methyl-4-oxocyclohexane-1-carboxylate. To a solution of ethyl8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (1 equiv.) inacetone/H₂O (0.5 M, 1/1) was added pTSA H₂O (1 equiv.). The mixture wasrefluxed overnight, then concentrated to remove acetone. The resultingsolution was diluted with ethyl acetate, and the layers were separated.The organic phase was washed with saturated NaHCO₃, dried over Na₂SO₄and filtered. The filtrate was concentrated to afford ethyl1-methyl-4-oxocyclohexanecarboxylate (67%). ¹ NMR (400 MHz, CDCl₃) δppm: 4.23 (q, J=7.2 Hz, 2H), 2.49-2.39 (m, 4H), 2.37-2.27 (m, 2H),1.75-1.64 (m, 2H), 1.34-1.28 (m, 6H).

Ethyl 4-(hydroxyimino)-1-methylcyclohexane-1-carboxylate. To a solutionof ethyl 1-methyl-4-oxocyclohexane-1-carboxylate (1.8 g, 9.78 mmol) inCH₃OH/H₂O (0.3 M, 4/1) were added NH₂OH.HCl (1.1 equiv.) and NaOAc (1.1equiv). The reaction was refluxed overnight and evaporated to removeMeOH. The resulting residue was diluted with water, and extracted withethyl acetate. The combined extracts were evaporated in vacuo.Purification of the residue by column chromatography on silica gel gaveethyl 4-(hydroxyimino)-1-methylcyclohexane-1-carboxylate (72%). ¹H NMR(400 MHz, CDCl₃) δ ppm: 4.20 (q, J=7.1 Hz, 2H), 3.04 (td, J=4.5, 15.1Hz, 1H), 2.38-2.21 (m, 4H), 2.20-2.08 (m, 1H), 1.53-1.37 (m, 2H), 1.29(t, J=7.0 Hz, 2H), 1.24 (s, 3H).

Ethyl 4-amino-1-methylcyclohexane-1-carboxylate hydrochloride. To asolution of ethyl 4-(hydroxyimino)-1-methylcyclohexane-1-carboxylate (1equiv.) in MeOH (0.3 M) was added Raney-Ni under N₂ atmosphere. Thesuspension was degassed under vacuum and purged with several times, andstirred at 50° C. under 50 psi of H₂ overnight. The reaction wasfiltered through a pad of celite, washed with MeOH, and treated with 4 MHCl/Dioxane. The resulting solution was evaporated under reducedpressure to afford ethyl 4-amino-1-methylcyclohexane-1-carboxylatehydrochloride (77%).

Ethyl(1r,4r)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylateand ethyl(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate.To a cooled (−78° C.) solution of 2,4-dichloro-5-nitropyrimidine (1equiv.) and ethyl 4-amino-1-methylcyclohexane-1-carboxylatehydrochloride (1 equiv.) in anhydrous THF (0.46 M) was added DIEA (3equiv.) dropwise over 30 min. After the addition, stirring was continuedfor 45 min at −78° C., then for 2 h at room temperature. The mixture wasdiluted with ethyl acetate, washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified to afford ethyl(1r,4r)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(46%), ¹H NMR (400 MHz, Benzene-d₆) δ ppm: 8.55 (s, 1H), 8.08 (d, J=6.8Hz, 1H), 4.03 (q, J=7.1 Hz, 2H), 3.97-3.80 (m, 1H), 1.87 (ddd, J=3.8,9.5, 13.6 Hz, 2H), 1.68-1.57 (m, 2H), 1.48-1.37 (m, 2H), 1.32-1.18 (m,2H), 1.09 (s, 3H), 1.04 (t, J=7.1 Hz, 3H); and ethyl(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(27%), ¹H NMR (400 MHz, Benzene-d₆) δ ppm: 8.44 (s, 1H), 7.85 (d, J=7.0Hz, 1H), 4.00-3.90 (m, 2H), 3.79 (tdt, J=4.0, 7.7, 11.6 Hz, 1H),2.19-2.07 (m, 2H), 1.76-1.65 (m, 2H), 1.36-1.22 (m, 2H), 0.98 (s, 2H),0.95-0.90 (m, 2H), 0.85 (dt, J=3.6, 13.4 Hz, 1H).

Ethyl(1s,4s)-1-methyl-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate.To a solution of ethyl(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylatecarboxylate(1.0 equiv.) in anhydrous DMF (0.4 M) were addedtetrahydro-2H-pyran-4-amine hydrochloride (1.2 equiv.) and DIEA (3equiv.). The mixture was stirred at room temperature for 3 h. Thereaction was diluted with ethyl acetate, the organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The resultingresidue was slurried with ethyl acetate and filtered to afford ethyl(1s,4s)-1-methyl-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate(80%). MS (ESI) m/z=408.1 [M+H]⁺.

Ethyl(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate.To a solution of ethyl(1s,4s)-1-methyl-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate(1 equiv.) in MeOH (0.1 M) was added Pd/C (0.1 g, 10% Pd by wt.) underN₂. The suspension was degassed under vacuum and purged with hydrogen.The suspension was stirred under hydrogen balloon at room temperaturefor 3 h. The reaction was filtered through a pad of celite, and washedwith MeOH. The filtrate was concentrated to afford ethyl(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(100%).

Ethyl(1s,4s)-1-methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylate.To a solution of ethyl(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(1 equiv.) in anhydrous DMF (0.36 M) was added1,3,5-trifluoro-2-isothiocyanatobenzene (1 equiv.), and the reaction wasstirred at room temperature for 90 min. DIC (2 equiv.) was added andstirring was continued at room temperature. The reaction was dilutedwith water, and extracted with ethyl acetate. The combined extracts wereevaporated. The resulting residue was purified by column chromatographyto afford ethyl(1s,4s)-1-methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylate(49%). MS (ESI) m/z=533.3 [M+H]⁺.

(1s,4s)-1-Methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylicacid. To ethyl(1s,4s)-1-methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylate(1 equiv.) in MeOH/H₂O (0.1 M, 4/1) was added KOH (8 equiv.). Thereaction was refluxed for 72 h. The reaction was concentrated, dilutedwith water, and extracted with ethyl acetate. The aqueous layer wasacidified with 6 M HCl to pH=3-5, and extracted with ethyl acetate. Thecombined extracts were evaporated under reduced pressure to afford(1s,4s)-1-methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylicacid (70%).

(1s,4s)-1-Methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-1-methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylicacid (1 equiv.) in DMF (0.2 M) were added HATU (2 equiv.), TEA (2equiv.) and NH₄Cl (2 equiv.). The reaction was stirred at roomtemperature overnight. Standard work-up and purification methodsafforded(1s,4s)-1-Methyl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(56%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.01 (s, 1H), 7.02 (s, 2H),4.33 (s, 1H), 4.08-3.93 (m, 3H), 3.72 (t, J=11.2 Hz, 2H), 2.91-2.66 (m,2H), 2.43-2.40 (m, 2H), 2.05-2.01 (m, 2H), 1.85-1.82 (m, 2H), 1.65-1.53(m, 2H), 1.46-1.43(m, 2H), 1.26 (s,3H). MS (ESI) m/z=504.2 [M+H]⁺.

Example 23(1s,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

2,4-Dichloro-6-fluoro-aniline. To a solution of 2-fluoroaniline (1equiv.) in MeOH (0.9 M) was added NCS (1 equiv.) in portions at 65° C.under N₂. The mixture was stirred at this temperature for 60 min. Themixture was evaporated to remove MeOH, diluted with ethyl acetate andfiltered to afford the crude product. Purification via silica gelchromatography provided product. Trituration of the material withpetroleum ether at 0° C. yielded 2,4-dichloro-6-fluoro-aniline (36%). ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.07 (s, 1H), 6.94-6.97 (m, 1H), 4.06 (s,2H).

1,5-Dichloro-3-fluoro-2-isothiocyanatobenzene. To a solution of2,4-dichloro-6-fluoro-aniline (1 equiv.) in anhydrous toluene (0.76 M)was added a catalytic amount of DMF (0.05 equiv.) and thiocarbonyldichloride (2.5 equiv.) drop-wise over 10 min under nitrogen. Themixture was slowly heated at 90˜100° C. for 2 h. After 2 h, the reactionwas complete. The mixture was filtered and the filtrate was concentratedto give crude product, which was purified by silica gel columnchromatography to give 1,5-dichloro-3-fluoro-2-isothiocyanato-benzene(66%). ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.25-7.28 (m, 1H), 7.11 (d, J=2.0Hz, 1H).

Methyl(1s,4s)-44(5-(3-(2,4-dichloro-6-fluorophenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate.To a solution of ethyl(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(1 equiv.) (prepared as described herein) in DMF (0.28 M) was added1,5-dichloro-3-fluoro-2-isothiocyanatobenzene (1.1 equiv.). The reactionwas stirred at 25° C. for 2 h. The mixture was used directly in the nextstep without further purification. DIC (2 equiv.) was added to thereaction mixture and stirring was continued at 40° C. for 16 h. LCMSshowed the reaction was complete. To the mixture was added brine, andthe precipitate was filtered. The filter cake was crystallized withethyl acetate to give (1s,4s)-methyl4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxylate(65%) as a white solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.01 (s,1H), 7.62-7.13 (m, 2H), 4.57-4.28 (m, 1H), 4.12-4.02 (m, 1H), 4.02-3.94(m, 2H), 3.78 (s, 3H), 3.76-3.64 (m, 2H), 2.89-2.63 (m, 3H), 2.42-2.28(m, 2H), 2.07-1.94 (m, 2H), 1.89-1.67 (m, 4H), 1.63-1.49 (m, 2H). MS(ESI) m/z=537.2 [M+H]⁺.

(1s,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxylicacid. To a mixture of (1s,4s)-methyl4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxylate(1 equiv.) in THF/water (5/1, 0.5 M) was added LiOH (5 equiv.). Thereaction was stirred at 60° C. for 16 h. Water was added to the mixtureand the pH was adjusted to 6 by addition of 1N HCl, then the mixture wasconcentrated to give crude product which was used directly in next stepwithout further purification. MS (ESI) m/z=523.1 [M+H]⁺.

(1s,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of(1s,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxylicacid (1 equiv.) in DMF (1.2 M) was added DIEA (2 equiv.), HATU (436 mg,1.15 mmol) and NH₄Cl (1.2 equiv.). The reaction was stirred at roomtemperature for 2 h. Standard work-up and purification methods afforded(1s,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(16%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 10.32 (brs, 1H), 7.61 (s,1H), 7.48-7.37 (m, 1H), 7.27-7.14 (m, 1H), 6.77-6.66 (m, 1H), 6.57-6.45(m, 1H), 4.45-4.30 (m, 1H), 3.92-3.76 (m, 3H), 3.61-3.44 (m, 2H),2.71-2.55 (m, 2H), 2.45-2.39 (m, 1H), 2.27-2.16 (m, 2H), 1.90-1.77 (m,2H), 1.72-1.36 (m, 6H). MS (ESI) m/z=522.2 [M+H]⁺.

Example 24(1s,4s)-4-(8-((2-Chloro-3-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

2-Chloro-3-methylaniline. To 2-chloro-1-methyl-3-nitrobenzene (1 equiv.)in acetic acid (0. 5M) was added Fe (4 equiv.). The reaction was heatedat 100° C. for 2 h. The solvent was removed and MeOH was added to theresidue. The mixture was stirred at room temperature for 12 h thenfiltered. The filtrate was concentrated and purified by silica gelchromatography to give 2-chloro-3-methylaniline (60%) as a red oil. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 6.90 (t, J=7.7 Hz, 1H), 6.66 (d, J=7.9 Hz,1H), 6.50 (d, J=7.4 Hz, 1H), 5.23 (brs, 2H), 2.24 (s, 3H).

2-Chloro-1-isothiocyanato-3-methylbenzene. To 2-chloro-3-methylaniline(1 equiv.) in DCM/water (0.5 M, 1/2) at 0° C. was added NaOH (3 equiv.),the solution was stirred at 0° C. for 5 min, then CSCl₂ (3 equiv.) wasadded. The reaction was stirred at room temperature overnight. Thereaction was extracted with DCM. The combined organic layers wereconcentrated to dryness to give crude2-chloro-1-isothiocyanato-3-methylbenzene. The crude product waspurified by column chromatography on silica gel with petroleum ether togive 2-chloro-1-isothiocyanato-3-methylbenzene (61%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ ppm: 7.19-7.09 (m, 3H), 2.42 (s, 3H).

cis-4-(84(2-Chloro-3-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of(1s,4s)-44(5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) (prepared as described herein) in DMF (0.3 M) was added2-chloro-1-isothiocyanato-3-methylbenzene (1.1 equiv.). The reaction wasstirred for 2 h at room temperature, and then DIC (3 equiv.) was added,and the reaction was stirred at room temperature overnight. Standardwork-up and purification methods afforded(1s,4s)-4-(8-((2-chloro-3-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(58%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.07 (s, 1H), 7.48-7.34 (m,1H), 7.24 (t, J=7.7 Hz, 1H), 7.16 (d, J=7.4 Hz, 1H), 4.38 (t, J=11.8 Hz,1H), 4.10-3.94 (m, 3H), 3.77-3.65 (m, 2H), 2.96-2.81 (m, 2H), 2.71-2.63(m, 1H), 2.44 (s, 3H), 2.34 (d, J=13.4 Hz, 2H), 2.05 (d, J=10.5 Hz, 2H),1.88-1.72 (m, 4H), 1.65-1.52 (m, 2H). MS (ESI) m/z=484.2 [M+H]⁺.

Example 25(1s,4s)-4-(8-((4-Chloro-2-fluoro-5-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

1-Chloro-5-fluoro-2-methyl-4-nitrobenzene. To a cooled (−5° C.) solutionof 2-fluoro-5-methylaniline (1 equiv.) in concentrated H₂SO₄ (0.7 M) wasadded KNO₃ (1.3 equiv.) in several portions within 1 h. The reaction wasallowed to warm to room temperature and stirred overnight. The reactionmixture was poured into ice-water slowly, and extracted with MTBE,washed with saturated NaHCO₃ and brine, dried over Na₂SO₄, filtered andconcentrated. The resulted residue was recrystallized from ethyl acetateand petroleum ether to afford 1-chloro-5-fluoro-2-methyl-4-nitrobenzene(61%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.00 (d, J=8.0Hz, 1H), 7.35 (d, J=10.4 Hz, 1H), 2.45 (s, 3H).

4-Chloro-2-fluoro-5-methylaniline. To a suspension of1-chloro-5-fluoro-2-methyl-4-nitrobenzene (1 equiv) in EtOH (2 M) wasadded Fe (5 equiv.), followed by concentrated HCl (2 M). The reactionwas refluxed for 3 h. The reaction was filtered through a pad of celite.The filtrate was concentrated. The resulting residue was purified bycolumn chromatography to afford 4-chloro-2-fluoro-5-methylaniline (32%)as a purple solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.41 (d, J=7.03 Hz,1H), 6.97-7.13 (m, 2H), 2.33 (s, 3H).

1-Chloro-5-fluoro-4-isothiocyanato-2-methylbenzene. To a cooled solutionof 4-chloro-2-fluoro-5-methylaniline 3 (1.0 g, 6.3 mmol) in DCM/H₂O (0.6M, 1/1) was added NaOH (3 equiv.), followed by dropwise addition ofSCCl₂ (3 equiv.) for 10 min. After the addition, the mixture was stirredfor 60 min at room temperature. The filtrate was concentrated to afford1-chloro-5-fluoro-4-isothiocyanato-2-methylbenzene (75%) as a colorlessoil.

cis-4-(8-((5-Chloro-2-fluoro-4-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution ofcis-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein) in anhydrous DMF (0.3 M) wasadded 1-chloro-5-fluoro-4-isothiocyanato-2-methylbenzene (1 equiv.), andthe solution was stirred at room temperature for 90 min. DIC (3 equiv.)was added and stirring was continued at room temperature for 12 h.Standard work-up and purification methods affordedcis-4-(8-((5-chloro-2-fluoro-4-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(58%).

¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.09 (s, 1H), 7.55 (d, J=9.5 Hz,1H), 7.27 (d, J=10.0 Hz, 1H), 4.34 (d, J=15.6 Hz, 1H), 4.11-3.91 (m,3H), 3.80-3.63 (m, 2H), 2.98-2.80 (m, 2H), 2.67 (s, 1H), 2.46-2.26 (m,5H), 2.12-1.93 (m, 2H), 1.88-1.67 (m, 4H), 1.66-1.38 (m, 2H). MS (ESI)m/z=502.2 [M+H]⁺.

Example 26(1s,4s)-4-(8-((4-Chloro-2-fluoro-6-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

4-Chloro-2-fluoro-6-methylaniline. To a solution of2-fluoro-6-methylaniline (1 equiv.) in DMF (0.8 M) was added NCS (1.2equiv.). The reaction was stirred at room temperature. Water and ethylacetate were added to the solution and the layers were separated. Theorganic layer was washed with H₂O, dried with Na₂SO₄ and concentrated.The resulting residue was purified by column chromatography on silicagel to give 4-chloro-2-fluoro-6-methylaniline (58%) as a brown oil. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 10.33 (dd, J=10.8, 2.0 Hz, 1H), 6.87 (s,1H), 4.53 (brs. 2H), 2.11 (s, 3H).

5-Chloro-1-fluoro-2-isothiocyanato-3-methylbenzene. To a solution of4-chloro-2-fluoro-6-methylaniline (1 equiv.) in DCM/water (0.8 M, 1/2)at 0° C. was added NaOH (3 equiv.). The solution was stirred at 0° C.for 5 min and CSCl₂(2 equiv.) was added. The reaction was stirred atroom temperature for 3 h. The mixture was filtered through a pad ofsilica gel and the pad was washed with DCM. The combined filtrates wereconcentrated to dryness to give5-chloro-1-fluoro-2-isothiocyanato-3-methylbenzene (43%) as brown oil.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.52 (dd, J=9.2, 2.4 Hz, 1H), 2.35 (s,3H).

(1s,4s)-4-(8-((4-Chloro-2-fluoro-6-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) (prepared as described herein) in DMF (0.3 M) was added5-chloro-1-fluoro-2-isothiocyanato-3-methylbenzene (1.1 equiv.). Thereaction was stirred at room for 2 h then DIC (3 equiv.) was added. Thereaction was stirred at room temperature overnight. Standard work-up andpurification methods affordedcis-4-(8-((4-chloro-2-fluoro-6-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(30%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.01-7.93 (m, 1H), 7.24-7.12(m, 2H), 4.50-4.33 (m, 1H), 4.10-3.95 (m, 3H), 3.75-3.65 (m, 2H),2.98-2.83 (m, 2H), 2.72-2.65 (m, 1H), 2.34 (d, J=14.1 Hz, 2H), 2.27 (s,3H), 2.06-1.99 (m, 2H), 1.82 (d, J=11.2 Hz, 4H), 1.64-1.50 (m, 2H). MS(ESI) m/z=502.2 [M+H]⁺.

Example 27(1s,4s)-4-(8-((2,3-Dichloro-4-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

2,3-Dichloro-4-methylaniline. To a solution of 3-chloro-4-methylaniline(1 equiv.) in DMF (0.7 M) at 0° C. was added NCS (1 equiv.) in DMFdropwise. The reaction was stirred at room temperature overnight. Waterand ethyl acetate was added to the solution and the layers wereseparated. The organic layer was washed with H₂O, dried over Na₂SO₄ andconcentrated. The resulting residue was purified by columnchromatography on silica gel to give 2,3-dichloro-4-methylaniline (26%).¹H NMR (400 MHz, DMSO-d₆) δ ppm: 6.98 (d, J=8.4 Hz, 1H), 6.69 (d, J=8.4Hz, 1H), 5.41 (brs. 2H), 2.20 (s, 3H). and 2,5-dichloro-4-methylaniline(16%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.17 (s, 1H), 6.85 (s, 1H), 5.38(brs. 2H), 2.15 (s, 3H).

2,3-Dichloro-1-isothiocyanato-4-methylbenzene. To a solution of2,3-dichloro-4-methylaniline (500 mg, 2.86 mmol) in DCM/water (0.4 M,1/2) at 0° C. was added NaOH (3 equiv.) and H₂O (4 mL). The solution wasstirred at 0° C. for 5 min then CSCl₂(3 equiv.) was added. The reactionwas stirred at room temperature for 3 h. The mixture was filteredthrough a pad of celite and the pad was washed with DCM. The combinedfiltrates were concentrated to dryness to give crude2,3-dichloro-1-isothiocyanato-4-methylbenzene. The crude product waspurified by silica gel chromatography to give2,3-dichloro-1-isothiocyanato-4-methylbenzene (66%) as a colorless oil.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.48-7.40 (m, 2H), 2.40 (s, 3H).

(1s,4s)-4-(84(2,3-Dichloro-4-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) (prepared as described herein) in DMF (0.3 M) was added2,3-dichloro-1-isothiocyanato-4-methylbenzene (1.1 equiv.). The reactionwas stirred at room temperature for 2 h. DIC (2 equiv.) was added andthe reaction was stirred at room temperature overnight. Standard work-upand purification methods afforded (1s,4s)-4-(8-((2,3-Dichloro-4-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(38%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.07 (s, 1H), 7.43 (d, J=8.0Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 4.43-4.30 (m, 1H), 4.10-3.94 (m, 3H),3.71 (t, J=10.9 Hz, 2H), 2.96-2.81 (m, 2H), 2.72-2.64 (m, 1H), 2.45 (s,3H), 2.39-2.29 (m, 2H), 2.04 (d, J=11.4 Hz, 2H), 1.88-1.72 (m, 4H),1.65-1.52 (m, 2H). MS (ESI) m/z=518.2 [M+H]⁺.

Example 28(1s,4s)-4-(8-((4-chloro-2-fluoro-3-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

4-Chloro-2-fluoro-3-methylaniline. To a solution of2-fluoro-3-methylaniline (1 equiv.) in DMF (0.8 M) was added NCS (1equiv.). The reaction was stirred at room temperature overnight. Waterand ethyl acetate was added to the solution and the layers wereseparated. The organic layer was washed with H₂O, dried over Na₂SO₄ andconcentrated. The resulting residue was purified by columnchromatography on silica gel to give 4-chloro-2-fluoro-3-methylaniline(22%) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.92 (dd, J=1.2, 8.4Hz, 1H), 6.61 (t, J=9.2 Hz, 1H), 5.20 (s, 2H), 2.18 (d, J=2.5 Hz, 3H).

1-Chloro-2-fluoro-4-isothiocyanato-3-methylbenzene. To a solution of4-chloro-2-fluoro-3-methylaniline (1 equiv.) in DCM/water (0.3 M, 1/2)at 0° C. was added NaOH (7 equiv.). The solution was stirred at 0° C.for 5 min. CSCl₂(7 equiv.) was added. The reaction was stirred at roomtemperature for 3 h. The mixture was filtered through a pad of silicagel and the pad was washed with DCM. The combined filtrates wereconcentrated to dryness to give1-chloro-2-fluoro-4-isothiocyanato-3-methylbenzene (91%) as brown oil.¹H NMR (400 MHz, CDCl₃) δ ppm: 7.38-7.34 (m, 2H), 2.28 (d, J=2.4 Hz,3H).

(1s,4s)-4-(8-((4-chloro-2-fluoro-3-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) (prepared as described herein) in DMF (0.4 M) was added1-chloro-2-fluoro-4-isothiocyanato-3-methylbenzene (1.1 equiv.). Thereaction was stirred at room temperature for 2 hours then DIC (3 equiv.)was added. The reaction was stirred at room temperature overnight.Standard work-up and purification methods afforded(1s,4s)-4-(8-((4-chloro-2-fluoro-3-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(40%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.08 (s, 1H), 7.43 (t, J=8.4Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 4.43-4.28 (m, 1H), 4.11-3.93 (m, 3H),3.78-3.65 (m, 2H), 2.98-2.78 (m, 2H), 2.73-2.63 (m, 1H), 2.40-2.27 (m,5H), 2.04 (d, J=10.4 Hz, 2H), 1.85-1.70 (m, 4H), 1.66-1.50 (m, 2H). MS(ESI) m/z=502.2 [M+H]⁺.

Example 29(1s,4s)-4-(8-((2,3-Dichloro-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

4-Bromo-5-chloro-2-fluoroaniline. To a mixture of5-chloro-2-fluoroaniline (1 equiv.) in acetonitrile (0.5 M) was addedN-bromosuccinimide (1 equiv.) at 25° C. The mixture was stirred at 25°C. for 1 h. The mixture was concentrated to a residue, the residue waspurified via silica gel chromatography to give4-bromo-5-chloro-2-fluoroaniline (91%) as a yellow oil. ¹H NMR (400 MHz,CDCl₃) δ ppm: 7.23 (d, J=10.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 3.92-2.64(br, 2H).

4-Bromo-2,3-dichloro-6-fluoroaniline. To a mixture of4-bromo-5-chloro-2-fluoroaniline (1 equiv.) in acetonitrile (0.36 M) wasadded NCS (1 equiv.) portion-wise at 90° C. over 30 min. The mixture wasstirred at 90° C. for 1 h. The residue was purified by chromatography togive 4-bromo-2,3-dichloro-6-fluoroaniline (76%) as a brown solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 7.35 (d, J=10.5 Hz, 1H).

2,3-Dichloro-6-fluoroaniline. To a mixture of4-bromo-2,3-dichloro-6-fluoroaniline (1 equiv.) in THF (0.28 M) wasadded n-BuLi (2 equiv.) dropwise at −78° C. over 10 min. After addition,the mixture was warmed to −30° C. and stirred for 1 h, and then themixture was cooled to −78° C. To the mixture was added H₂O. The mixturewas warmed to 25° C., and extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated to givea residue. The residue was purified by chromatography to give2,3-dichloro-6-fluoroaniline (43%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ ppm: 6.93-6.85 (m, 1H), 6.83-6.76 (m, 1H), 4.23 (brs., 2H)

1,2-Dichloro-4-fluoro-3-isothiocyanatobenzene. To a mixture of2,3-dichloro-6-fluoroaniline (1 equiv.) in DCM (0.1 M, 1/2) was addedNaOH (5 equiv.) and SCCl₂ (3 equiv.) at 0° C. After addition, themixture was allowed to warm to room temperature and stirred for 16 h.The mixture was filtered, and the filtrate was extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, and concentrated to aresidue. The residue was purified by chromatography to give1,2-dichloro-4-fluoro-3-isothiocyanatobenzene (59%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ ppm: 7.05 (t, J=8.78 Hz, 1H) 7.33 (dd, J=9.03,5.14 Hz, 1H)cis-4-(8-((2,3-Dichloro-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) (prepared as described herein) in DMF (0.8 M) was added1,2-dichloro-4-fluoro-3-isothiocyanatobenzene (1 equiv.). The reactionmixture was stirred at 25° C. for 1 h. DIC (2 equiv.) was added andstirring continued at 25° C. for 16 h. Standard work-up and purificationmethods afforded(1s,4s)-4-(8-((2,3-dichloro-6-fluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(38%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.79 (s, 1H), 7.39-7.32 (m,1H), 7.20 (t, J=9.1 Hz, 1H), 4.58-4.39 (m, 1H), 4.11-3.90 (m, 3H),3.81-3.61 (m, 2H), 2.97-2.79 (m, 2H), 2.67 (s, 1H), 2.34 (d, J=13.8 Hz,2H), 2.13-1.98 (m, 2H), 1.88-1.70 (m, 4H), 1.64-1.49 (m, 2H). MS (ESI)m/z=522.4 [M+H]⁺.

Example 30(1s,4s)-4-(8-((4-Chloro-3-fluoro-2-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.

4-Chloro-3-fluoro-2-methylaniline. To a solution of3-fluoro-2-methylaniline (1 equiv.) in DMF (0.8 M) was added NCS (1equiv.). The reaction was stirred at room temperature overnight. Waterand ethyl acetate were added to the solution and the layers wereseparated. The organic layer was washed with H₂O, dried over Na₂SO₄ andconcentrated. The resulting residue was purified by columnchromatography on silica gel to give 4-chloro-3-fluoro-2-methylaniline(12%) as a brown oil. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.02 (t, J=8.0 Hz,1H), 6.42 (dd, J=1.6, 8.8 Hz, 1H), 3.71 (brs, 2H), 2.11 (d, J=1.6 Hz,3H).

1-Chloro-2-fluoro-4-isothiocyanato-3-methylbenzene. To a solution of4-chloro-3-fluoro-2-methylaniline (1 equiv.) in DCM/water (0.3 M, 1/2)at 0° C. was added NaOH (2 equiv.). The solution was stirred at 0° C.for 5 min then CSCl₂(2 equiv.) was added. The reaction was stirred atroom temperature for 3 h. The mixture was filtered through a pad ofsilica gel and the pad was washed with DCM. The combined filtrates wereconcentrated to dryness to give1-chloro-2-fluoro-4-isothiocyanato-3-methylbenzene (75%) as a brown oil.¹H NMR (400 MHz, CDCl₃) δ ppm: 7.22 (t, J=8.0 Hz, 1H), 7.00 (dd, J=1.6,8.4 Hz, 1H), 2.35 (d, J=2.4 Hz, 3H).

(1s,4s)-4-(8-((4-Chloro-3-fluoro-2-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) (prepared as described herein) in DMF (0.4 M) was added1-chloro-2-fluoro-4-isothiocyanato-3-methylbenzene (1.1 equiv.). Thereaction was stirred at room temperature for 2 h then DIC (3 equiv.) wasadded. The reaction was stirred at room temperature overnight. Standardwork-up and purification methods afforded(1s,4s)-4-(8-((4-chloro-3-fluoro-2-methylphenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(31%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.00 (s, 1H), 7.33 (t, J=8.4Hz, 1H), 7.18-7.05 (m, 1H), 4.44-4.30 (m, 1H), 4.11-3.91 (m, 3H),3.79-3.64 (m, 2H), 2.98-2.82 (m, 2H), 2.73-2.63 (m, 1H), 2.34 (d, J=14.1Hz, 2H), 2.18 (d, J=2.4 Hz, 3H), 2.09-1.98 (m, 2H), 1.87-1.72 (m, 4H),1.65-1.50 (m, 2H). MS (ESI) m/z=502.2 [M+H]⁺.

Example 31(1s,4s)-4-(8-((6-Chloro-2,3-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

4-Bromo-2,3-difluoroaniline. To a solution of 2,3-difluoroaniline (1equiv.), N-bromosuccinimide (1 equiv.) in acetonitrile (1 M). Themixture was stirred at 35° C. for 2 h, and then reduced in vacuo toafford a residue. The residue was poured into water and extracted withethyl acetate, then concentrated to give the crude product, which waspurified by silica gel chromatography to afford the desired product4-bromo-2,3-difluoroaniline (68%).

4-Bromo-6-chloro-2,3-difluoroaniline. To a solution of4-bromo-2,3-difluoroaniline (1 equiv.) in acetonitrile (3 M). Thesolution was warmed to reflux, and then NCS (1.1 equiv.) was added inportions. The reaction was stirred at 70° C. The solution wasconcentrated in vacuo to give a residue, which was poured into water,extracted with ethyl acetate. The organics were collected, concentratedto give crude product. The crude product was purified by silica gelcolumn to give the desired product 4-bromo-6-chloro-2,3-difluoroaniline(78%). ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.24-7.22 (m, 1H), 4.21 (brs, 2H).

6-Chloro-2,3-difluoroaniline. To a solution of4-bromo-6-chloro-2,3-difluoroaniline (1 equiv.) in THF (1.6 M). Thesolution was cooled to −78° C. and then n-BuLi (2 equiv.) was addeddrop-wise. The reaction was stirred at −78° C. for 1.5 h, and thenquenched with water. The solution was extracted with ethyl acetate. Theorganic layer was concentrated in vacuo to afford the crude product,which was purified by silica gel column to give the desired product6-chloro-2,3-difluoroaniline (55%). ¹H NMR (400 MHz, CDCl₃) δ ppm:6.99-6.95 (m, 1H), 6.53-6.48 (m, 1H), 4.19 (brs, 2H).

(1s,4s)-4-(8-((6-Chloro-2,3-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of 6-chloro-2,3-difluoroaniline (1 equiv.), KOH (6 equiv.)in DCM/H₂O (1.2 M, 1/2). The solution was cooled to 0° C. and stirredfor 20 min, and then SCCl₂ (6 equiv.) was added drop-wise. The reactionwas stirred at 36° C.-40° C. for 10 h. The solution was extracted withethyl acetate. The organic layer was concentrated in vacuo to get thecrude product, which was used directly into the next step withoutfurther purification. To a solution of1-chloro-3,4-difluoro-2-isothiocyanatobenzene (1 equiv.) and(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) (prepared as described herein) in DMF (1.2 M), DIC (2 equiv.)was added drop wise. The reaction was stirred at 31° C.-35° C. for 12 h.Standard work-up and purification methods provided(1s,4s)-4-(8-((6-chloro-2,3-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(23%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.37 (br. s., 1H) 7.65 (br. s.,1H) 7.30 (br. s., 1H) 7.20 (br. s., 1H) 7.07 (br. s., 1H) 6.71 (br. s.,1H) 6.51 (br. s., 1H) 4.40 (t, J=11.86 Hz, 1H) 3.80-3.94 (m, 3H) 3.52(d, J=10.92 Hz, 2H) 2.55-2.77 (m, 2H) 2.44 (br. s., 1H) 2.24 (d, J=13.20Hz, 2H) 1.84 (d, J=12.80 Hz, 2H) 1.38-1.70 (m, 6H). MS (ESI) m/z=506.1[M+H]⁺.

Example 32(1S,4s)-4-(2-(((3S,4R)-3-Fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

4,4-Dimethoxytetrahydro-2H-pyran. CH(OMe)₃ (1.2 equiv) was addeddropwise over a period of 20 min to a solution ofdihydro-2H-pyran-4(3H)-one (1 equiv.) and pTSA (0.03 equiv.) inanhydrous MeOH (8 M), while the reactants were maintained under gentlerefluxing. After 15 min, the products were neutralized with sodiummethoxide/MeOH (1 M) and distilled to give4,4-dimethoxytetrahydro-2H-pyran (41%) as a colorless oil. ¹H NMR (400MHz, CDCl₃) δ ppm: 3.68 (t, J=5.2 Hz, 4H), 3.22 (s, 6H), 1.77 (t, J=5.6Hz, 4H).

4-Methoxy-3,6-dihydro-2H-pyran. 4,4-dimethoxytetrahydro-2H-pyran (1equiv.) and pTSA (0.01 equiv.) were placed together in a distillationapparatus. The reaction was heated (bath temperature: 160° C.) atatmospheric pressure. When the theoretical amount of MeOH had beencollected, the reaction was distilled under reduced pressure (waterpump) to give 4-methoxy-3,6-dihydro-2H-pyran (21%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ ppm: 4.55-4.68 (m, 1H), 4.20 (q, J=2.3 Hz,2H), 3.80-3.87 (m, 2H), 3.53-3.57 (m, 3H), 2.19 (ttd, J=5.6 Hz, 2.2 Hz,1.1 Hz, 2H).

3-Fluorodihydro-2H-pyran-4(3H)-one. To a solution of SelectFluor (0.85equiv.) in acetonitrile/H₂O (1/1, 0.4 M) was added a solution of4-methoxy-3,6-dihydro-2H-pyran (1 equiv.) in acetonitrile dropwisekeeping the temperature at 0-5° C. After the addition, the reaction wasstirred at 0° C. for 30 min, and the reaction was stirred at roomtemperature for 24 h. Solid NaCl (40.0 g) was added, the mixture wasextracted with MTBE, dried over Na₂SO₄, filtered and concentrated toafford 3-fluorodihydro-2H-pyran-4(3H)-one (42%) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ ppm: 4.85-5.05 (m, 1H), 4.36-4.42 (m, 1H),4.16-4.24 (m, 1H), 3.60-3.78 (m, 2H), 2.61-2.76 (m, 2H).

trans-N-Benzyl-3-fluorotetrahydro-2H-pyran-4-amine andcis-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine. To a cooled (0° C.)solution of 3-fluorodihydro-2H-pyran-4(3H)-one (1 equiv.) in MeOH (0.3M) was added benzylamine (1.05 equiv.), NaBH₃CN (1.4 equiv.) and aceticacid (1 equiv.). The reaction was stirred at room temperature overnight.The reaction was concentrated, diluted with water, extracted with ethylacetate, dried over Na₂SO₄, filtered and concentrated. The resultedresidue was purified with preparative HPLC to affordtrans-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine andcis-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine as a colorless oil.trans-diastereomer—¹H NMR (400 MHz, CDCl₃) δ ppm: 7.34-7.40 (m, 1H),7.25-7.33 (m, 1H), 4.33-4.54 (m, 1H), 4.08 (dt, J=11.1, 5.6 Hz, 1H),3.82-3.97 (m, 3H), 3.41 (td, J=11.4, 2.5 Hz, 1H), 3.33 (ddd, J=11.2,9.2, 4.6 Hz, 1H), 2.94 (dddd, J=11.4, 10.4, 8.2, 4.8 Hz, 1H), 2.00-2.09(m, 1H), 1.47-1.63 (m, 1H). cis-di asteromer NMR (400 MHz, CDCl₃) δ ppm:7.33-7.42 (m, 4H), 7.26-7.32 (m, 1H), 4.64-4.84 (m, 1H), 4.14-4.25 (m,1H), 4.03 (dtd, J=11.4, 3.6, 1.1 Hz, 1H), 3.82-3.97 (m, 2H), 3.52 (dd,J=13.1, 0.9 Hz, 1H), 3.37-3.46 (m, 2H), 2.72-2.86 (m, 1H), 1.80-1.88 (m,2H).

(3R,4S)-N-Benzyl-3-fluorotetrahydro-2H-pyran-4-amine and(3S,4R)-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine.trans-N-Benzyl-3-fluorotetrahydro-2H-pyran-4-amine was separated bychiral-HPLC (AD-3S_3_5_40_3ML Column: Chiralpak AD-3 100×4.6 mm I.D., 3um Mobile phase: MeOH (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3mL/min Wavelength: 220 nm) to afford(3R,4S)-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine and(3S,4R)-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine as a colorless oil.

(3R,4S)-3-Fluorotetrahydro-2H-pyran-4-amine hydrochloride. To a solutionof (3R,4S)-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine (1 equiv.) inanhydrous MeOH (0.3 M) was added Pd/C (0.1 equiv, 10% Pd by wt.) underN₂ atmosphere. The suspension was degassed under vacuum and purged withhydrogen several times. The reaction mixture was stirred under hydrogenballoon for 3 h at room temperature. Then the reaction was filteredthrough a pad of celite and washed with MeOH. The filtrate was treatedwith 4 M HCl and concentrated to afford(3R,4S)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride as a whitesolid (100%).

(3S,4R)-3-Fluorotetrahydro-2H-pyran-4-amine hydrochloride. To a solutionof (3S,4R)-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine (1 equiv.) inanhydrous MeOH (0.3 M) was added Pd/C (0.1 equiv., 10% Pd by wt.) underN₂ atmosphere. The suspension was degassed under vacuum and purged withhydrogen several times. The reaction mixture was stirred under hydrogenballoon for 3 h at room temperature. The reaction was filtered through apad of celite and washed with MeOH. The filtrate was treated with 4 MHCl and concentrated to afford(3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride as a whitesolid (100%).

(3R,4R)-N-Benzyl-3-fluorotetrahydro-2H-pyran-4-amine and(3S,4S)-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine.cis-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine was separated bychiral-HPLC (AS-3_S_5_5_40_3ML Column: Chiralpak AS-3 150×4.6 mm I.D., 3um Mobile phase: EtOH (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3mL/min Wavelength: 220 nm) to afford(3R,4R)-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine and(3S,4S)-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine as a colorless oil.

(3R,4R)-3-Fluorotetrahydro-2H-pyran-4-amine hydrochloride. To a solutionof (3R, 4R)-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine (1 equiv.) inanhydrous MeOH (0.2 M) was added Pd/C (0.1 equiv., 10% Pd/C) under N₂atmosphere. The suspension was degassed under vacuum and purged withhydrogen several times. The reaction mixture was stirred under hydrogenballoon for 3 h at room temperature. The reaction was filtered through apad of celite and washed with MeOH. The filtrate was treated with 4 MHCl and concentrated to afford (3R,4R)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride as a white solid(100%).

(3S,4S)-3-Fluorotetrahydro-2H-pyran-4-amine hydrochloride. To a solutionof (3S, 4S)-N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine (1 equiv.) inanhydrous MeOH (0.2 M) was added Pd/C (0.1 equiv., 10% Pd/C) under N₂atmosphere. The suspension was degassed under vacuum and purged withhydrogen several times. The reaction mixture was stirred under hydrogenballoon for 3 h at room temperature. The reaction was filtered through apad of celite and washed with MeOH. The filtrate was treated with 4 MHCl and concentrated to afford (3S,4S)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride a white solid(100%).

(1S,4R)-4-((2-(((3R,4S)-3-Fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamide.To a solution of(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) (prepared as described herein) in anhydrous DMF (0.3 M) wereadded (3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride (1equiv.) and DIEA (3 equiv.). The formed precipitated solid was collectedby filtration to give (1S,4R)-4-((2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamide(38%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.99-8.85 (m, 1H), 8.75-8.29 (m, 2H),7.35-7.14 (m, 1H), 6.87-6.65 (m, 1H), 4.65-3.78 (m, 5H), 3.49-3.41 (m,1H), 2.38-2.19 (m, 1H), 2.09-1.45 (m, 11H).

(1S,4r)-4-((5-Amino-2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide.To a solution of(1S,4R)-4-((2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamidein MeOH (0.1 M) was added Pd/C (0.1 equiv, 10% Pd/C) under nitrogenatmosphere. The suspension was degassed under vacuum and purged withhydrogen several times. The reaction mixture was stirred under hydrogenballoon for 16 h at room temperature. The reaction was filtered througha pad of celite and washed with MeOH. The filtrate was concentrated invacuum to afford(1S,4r)-4-((5-amino-2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamidea purple solid (88%). MS (ESI) m/z=353.1 [M+H]⁺.

(1S,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamideTo a solution of(1S,4r)-4-((5-amino-2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) in anhydrous DMF (0.2 M) was added1,3,5-trichloro-2-isothiocyanatobenzene (1 equiv.). The reaction wasstirred for 90 min at room temperature. Then DIC (1 equiv.) was addedand stirring was continued at room temperature overnight. Standardwork-up and purification methods provided(1S,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.29 (s, 1H), 8.10-7.56 (m, 2H),7.33-7.17 (m, 1H), 6.95-6.62 (m, 1H), 4.64-4.29 (m, 2H), 4.18 (s, 1H),4.00 (s, 1H), 3.79 (d, J=9.40 Hz, 1H), 3.60 (s, 1H), 3.48-3.42 (m, 1H),2.68 (t, J=12.42 Hz, 2H), 2.45-2.33 (m, 1H), 2.22 (s, 2H), 2.00 (d,J=11.92 Hz, 1H), 1.76-1.37 (m, 5H). MS (ESI) m/z=556.5 [M+H]⁺.

Example 33(1S,4s)-4-(8-9(2,4-Dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

(1S,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a mixture of(1S,4s)-4-((5-amino-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) in DMF (0.2 M) was added1,5-dichloro-3-fluoro-2-isothiocyanatobenzene (1.1 equiv., prepared asdescribed herein). The mixture was stirred at room temperature and DIC(2 equiv.) was added. The mixture was stirred at room temperature for 16h. Standard work-up and purification methods afforded(1S,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(34%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.37 (s, 1H), 7.66-7.45 (m, 2H),7.44-7.18 (m, 2H), 6.90-6.68 (m, 2H), 4.62-4.44 (m, 1H) 4.43-4.33 (m,1H) 4.19 (s, 1H) 4.05-3.96 (m, 1H) 3.80-3.65 (m, 1H) 3.64-3.58 (m, 1H)3.44-3.38 (m, 1H) 2.77-2.60 (m, 2H) 2.46-2.40 (m, 1H), 2.24-2.18 (m, 2H)2.05-1.97 (m, 1H) 1.71-1.42 (m, 5H). MS (ESI) m/z=540.1 [M+H]⁺.

Example 34(1S,4s)-4-(8-((2-Chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

(1S,4s)-4-(8-((2-Chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.To a mixture of(1S,4s)-4-((5-amino-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv., prepared as described herein) in DMF (0.24 M) was added1-chloro-3,5-difluoro-2-isothiocyanatobenzene (1 equiv.) in one portion.The mixture was stirred at room temperature for 3 h. DIC (2 equiv.) wasadded. The mixture was stirred at room temperature for 16 h, andstirring was continued at 30° C. for 14 h. Standard workup andpurification conditions afforded(1S,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(36%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm: 8.55-10.38 (m,1.0H) 7.55-8.21 (m, 0.9H) 7.40-7.51 (m, 0.8H) 7.24-7.40 (m, 1.6H) 7.20(br. s., 0.6H) 6.81 (d, J=8.2 Hz, 1.0H) 6.60-6.78 (m, 1.0H), 4.44-4.62(m, 1.0H) 4.33-4.44 (m, 1.0H) 4.11-4.28 (m, 1.0H) 3.93-4.06 (m, 1.0H)3.74-3.86 (m, 1.0H) 3.52-3.70 (m, 1.0H) 3.38-3.50 (m, 1.0H) 2.58-2.86(m, 2.1H) 2.36-2.48 (m, 1.2H) 2.15-2.31 (m, 2.0H) 1.93-2.10 (m, 1.0H)1.39-1.77 (m, 5.1H). MS (ESI) m/z=524.2 [M+H]⁺.

Example 35(1R,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

(1R,4s)-4-((2-(((3S,4S)-3-Fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) (prepared as described herein) in anhydrous DMF (0.3 M) wereadded (3S,4S)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride(prepared as described herein) (1.1 equiv.) and DIEA (3 equiv.). Theformed precipitated solid was collected by filtration to give(1R,4s)-4-((2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(100%). MS (ESI) m/z=383.1 [M+H]⁺.

(1R,4s)-4-((5-Amino-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide.To a solution of(1R,4s)-4-((2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) in MeOH (0.18 M) was added Pd/C (0.1 equiv., 10% Pd by wt.)under nitrogen atmosphere. The suspension was degassed under vacuum andpurged with hydrogen several times. The reaction mixture was stirredunder hydrogen balloon for 3 h at room temperature. The reaction wasfiltered through a pad of celite and washed with MeOH. The filtrate wasconcentrated in vacuum to afford(1R,4s)-4-((5-amino-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamideas a purple solid (100%).

(1R,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1R,4s)-4-((5-amino-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) in anhydrous DMF (0.2 M) was added1,5-dichloro-3-fluoro-2-isothiocyanatobenzene (prepared as describedherein) (1 equiv.). The reaction was stirred for 1 h at roomtemperature. DIC (1 equiv.) was added and stirring was continued for 18h at room temperature. Standard work-up and purification methodsafforded(1R,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(21%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.34 (s, 1H), 7.78-7.63 (m,2H), 7.25 (s, 1H), 6.77 (s, 1H), 6.56 (s, 1H), 4.81-4.64 (m, 1H), 4.40(s, 1H), 4.10-3.87(m, 4H), 3.90-3.52 (m, 1H), 2.70-2.58 (m, 2H), 2.45(s, 1H), 2.18 (s, 2H), 1.92-1.88(m, 1H), 1.63-1.56 (m, 5H). MS (ESI)m/z=540.2 [M+1]⁺.

Example 36(1R,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

(1R,4s)-4-((2-(((3S,4S)-3-Fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexanecarboxamide.To a mixture of(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1 equiv., prepared as described herein) and(3S,4S)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride (1.1 equiv.,prepared as described herein) in DMF (0.3 M) was added DIEA (3 equiv.)in one portion at 20° C. under N₂. The mixture was stirred at 20° C. for18 h. The mixture was diluted with ethyl acetate, the organic layer wasseparated, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was recrystallized from ethyl acetate toafford(1R,4s)-4-((2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexanecarboxamide(95%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.87 (s, 1H), 8.48-8.22 (m, 1H),8.12 (t, J=8.4 Hz, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 4.89-4.59 (m, 1H),4.34-3.82 (m, 4H), 3.64-3.44 (m, 2H), 2.23-2.08 (m, 2H), 2.04-1.91 (m,1H), 1.89-1.75 (m, 2H), 1.70-1.57 (m, 1H), 1.50-1.32 (m, 2H), 1.28-1.12(m, 2H), 1.07 (s, 3H).

(1R,4s)-4-((5-Amino-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexanecarboxamide.To a solution of(1R,4s)-4-((2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexanecarboxamide(1 equiv.) in MeOH (0.13 M) was added Pd/C (0.1 equiv, 10% Pd by wt.)under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred under H₂ (20 psi) at 20° C. for 3h. The reaction mixture was filtered and the filtrate was concentratedto give(1R,4s)-4-((5-amino-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexanecarboxamide(98%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.33 (s, 1H), 4.77-4.61 (m, 1H),4.15-3.95 (m, 3H), 3.95-3.85 (m, 1H), 3.54 (s, 2H), 2.28-2.18 (m, 2H),2.01-1.75 (m, 4H), 1.49-1.27 (m, 4H), 1.19 (s, 3H).

(1R,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.To a solution of(1R,4s)-4-((5-amino-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexanecarboxamide(1 equiv.) in anhydrous DMF (0.25 M) was added1,5-dichloro-3-fluoro-2-isothiocyanatobenzene (prepared as describedherein) (1.1 equiv.) and the mixture was stirred at 20° C. for 90 min.DIC (2 equiv.) was added and stirring was continued at 20° C. for 18 h.Standard work-up and purification methods afforded(1R,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide(41%). ¹H NMR (500 MHz, Methanol-d₄) δ ppm: 8.06 (s, 1H), 7.64-7.18 (m,2H), 4.84-4.65 (m, 1H), 4.59-4.33 (m, 1H), 4.29-3.99 (m, 3H), 3.98-3.72(m, 2H), 2.89-2.59 (m, 2H), 2.46-2.33 (m, 2H), 2.04-1.91 (m, 1H),1.91-1.76 (m, 3H), 1.52-1.38 (m, 2H), 1.26 (s, 3H). MS (ESI) m/z=554.1[M+1]⁺.

Example 37(1R,4s)-4-(2-(((3S,4S)-3-Fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

(1R,4s)-4-(2-(((3S,4S)-3-Fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution ofcis-4-((5-amino-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein) in anhydrous DMF (0.2 M) wasadded 1,3,5-trichloro-2-isothiocyanatobenzene (1 equiv.). The reactionwas stirred for 1 h at room temperature. DIC (1 equiv.) was added andstirring was continued for 18 h at room temperature. Standard work-upand purification methods affordedcis-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(21%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.34 (s, 1H), 7.78-7.63 (m,2H), 7.25 (s, 1H), 6.77 (s, 1H), 6.56 (s, 1H), 4.81-4.64 (m, 1H), 4.40(s, 1H), 4.10-3.87(m, 4H), 3.90-3.52 (m, 1H), 2.70-2.58 (m, 2H), 2.45(s, 1H), 2.18 (s, 2H), 1.92-1.88(m, 1H), 1.63-1.56 (m, 5H). MS (ESI)m/z=557.2 [M+1]⁺.

Example 38(1s,4s)-4-(8-((2,6-dichloro-4-cyanophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

3,5-Dichloro-4-isothiocyanatobenzonitrile. To a cooled (0° C.) solutionof 4-amino-3,5-dichlorobenzonitrile (1 equiv.) in anhydrous DCM (0.5 M)was added DIEA (3 equiv.) in one portion. SCCl₂ (3 equiv.) was addeddropwise over 20 min. After the addition, the reaction mixture wasstirred for about 5 h at 0° C. The solvent was evaporated to give abrown solid, which was purified by column chromatography on silica gel(petroleum/ethyl acetate=25/1) to give3,5-dichloro-4-isothiocyanatobenzonitrile as a light yellow solid (75%).

(1s,4s)-4-(8-((2,6-Dichloro-4-cyanophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of 3,5-dichloro-4-isothiocyanatobenzonitrile (1 equiv.) inanhydrous DMF (0.3 M) was addedcis-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein). After the addition, thereaction mixture was stirred for 1 h at room temperature. DIC (1 equiv.)was added in one portion. The reaction mixture stirred for 16 h at roomtemperature. Standard work-up and purification methods afforded(1s,4s)-4-(8-((2,6-dichloro-4-cyanophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(18%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.85-7.59 (m, 2H), 7.47 (s,1H), 4.61-4.42 (m, 1H), 4.00 (d, J=11.29 Hz, 3H), 3.68 (t, J=10.85 Hz,2H), 2.85 (d, J=10.79 Hz, 2H), 2.65 (s, 1H), 2.34 (d, J=14.31 Hz, 2H),2.08-1.93 (m, 2H), 1.80-1.68 (m, 4H), 1.65-1.49 (m, 2H). MS (ESI) m/z529.1 [M]⁺.

Example 39(1R,4s)-4-(8-((2,6-Dichloro-4-cyanophenyl)amino)-2-4(S)-1-hydroxypropan-2-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

(1R,4s)-4-((2-(((S)-1-hydroxypropan-2-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide.To a mixture of(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) (prepared as described herein) in DMF (0.3 M) was added(S)-2-aminopropan-1-ol (1 equiv.), DIEA (1 equiv.) at 25° C. The mixturewas stirred at room temperature for 12 h. The mixture was poured intowater and extracted with ethyl acetate. The organic solvents wereconcentrated to give the crude product. The solid was purified by columnchromatography to give(1R,4s)-4-((2-(((S)-1-hydroxypropan-2-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(69%) as a brown solid. MS (ESI) m/z=339.1 [M+H]⁺.

(1R,4s)-4-((5-Amino-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide.To a mixture of(1R,4s)-4-((2-(((S)-1-hydroxypropan-2-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) in MeOH (0.05 M) was added Pd/C (0.1 equiv., 10% Pd by wt.).The mixture was stirred under H₂ balloon at 25° C. for 12 h. The mixturewas filtered, the organic solvent was concentrated to give(1R,4s)-4-((5-amino-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(81%).

(1R,4s)-4-(8-((2,6-Dichloro-4-cyanophenyl)amino)-2-(((S)-1-hydroxypropan-2-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a solution of(1R,4s)-4-((5-amino-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) in DMF (0.4 M) was added3,5-dichloro-4-isothiocyanatobenzonitrile (1.1 equiv.) (prepared asdescribed herein). The reaction mixture was stirred at 30° C. for 2 h.To the reaction mixture was added DIC (2 equiv.), and the mixture wasstirred at 30° C. for 16 h. Standard work-up and purification methodsafforded(1R,4s)-4-(8-((2,6-dichloro-4-cyanophenyl)amino)-2-(((S)-1-hydroxypropan-2-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(31%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 10.49 (s, 1H), 8.01 (s, 2H),7.67 (s, 1H), 7.31 (s, 1H), 6.86 (s, 1H), 6.26 (s, 1H), 4.75-4.72 (m,1H), 4.37-4.35 (m, 1H), 3.82-3.90 (m, 1H), 3.51-3.59 (m, 1H), 3.24-3.10(m, 1H), 2.63-2.74 (m, 2H), 2.45 (s., 1H), 2.23-2.18 (m, 2H), 1.51-1.66(m, 4H), 1.14 (d, J=6.5 Hz, 3H). MS (ESI) m/z=503.1 [M+H]⁺.

Example 40(1S,4s)-4-(8-((4-Chloro-2,6-difluorophenyl)amino)-2-(((R)-3,3-difluorocyclopentyl)amino)-9H-purin-9-yl)cyclohexane-t-carboxamide

3-Azidocyclopentanone. To a mixture of TMSN₃ (5 equiv.) and acetic acid(5 equiv.) in DCM (1 M) was added cyclopent-2-enone (1 equiv.) and TEA(0.20 equiv.) in one portion at room temperature under N₂. The mixturewas stirred at room temperature for 18 h. To the mixture was addedsaturated NaHCO₃ and stirring was continued for 20 min, then the aqueousphase was extracted with DCM. The combined organic phase was washed withsaturated brine dried over anhydrous Na₂SO₄, filtered and concentratedin vacuum to give 3-azidocyclopentanone as a crude product. The crudeproduct was used directly in the next step without purification.

tert-Butyl (3-oxocyclopentyl)carbamate. To a solution of3-azidocyclopentanone (1.00 equiv.) in ethyl acetate (1.2 M) was addeddi-tert-butyl dicarbonate (1.20 equiv.) and Pd/C (0.1 equiv. 10% by wt.)under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred under H₂ (50 psi) at 15° C. for 5h. The reaction mixture was filtered and the filtrate was concentrated.The crude product was purified by silica gel chromatography (29%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 4.68-4.67 (m, 1H), 4.23 (s,1H), 2.66 (dd, J=18.45, 7.15 Hz, 1H), 2.38-2.34 (m, 2H), 2.25-2.13 (m,2H), 1.85-1.84 (m, 1H), 1.45 (s, 9H).

tert-Butyl (3,3-difluorocyclopentyl)carbamate. To a mixture oftert-butyl (3-oxocyclopentyl)carbamate (1 equiv.) in DCM (0.2 M) wasadded DAST (5.00 equiv.) in one portion at room temperature under N₂.The mixture was stirred at room temperature for 20 h. The mixture waspoured into ice-water (w/w=1/1) and stirred for 20 min. The aqueousphase was extracted with DCM. The combined organic phase was washed withsaturated brine, dried over anhydrous Na₂SO₄, filtered and concentratedin vacuum to give a residue. The residue was purified by silica gelchromatography to afford tert-butyl (3,3-difluorocyclopentyl)carbamate(36%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 4.68 (s, 1H),4.19-4.17 (m, 1H), 2.54 (qd, J=14.28, 7.97 Hz, 1H), 2.23-2.21 (m, 2H),2.21-2.09 (m, 2H), 1.70-1.68 (m, 1H), 1.46 (s, 9H).

3,3-Difluorocyclopentanamine hydrochloride. The mixture of tert-butyl(3,3-difluorocyclopentyl)carbamate (1 equiv.) in HCl/ethyl acetate (2.00equiv.) was stirred at room temperature for 1 h. The solid wasprecipitated. The mixture was filtered and the filter cake was dried invacuum to afford 3,3-difluorocyclopentanamine hydrochloride (73%) as awhite solid.

(R)-Benzyl (3,3-difluorocyclopentyl)carbamate and (S)-benzyl(3,3-difluorocyclopentyl)carbamate. To a mixture of3,3-difluorocyclopentanamine hydrochloride (1 equiv.) and CbzCl (1.5equiv.) in DCM (1.3 M) was added TEA (3 equiv.) in one portion. Themixture was stirred at room temperature for 2 h. To the mixture wasadded water, stirring was continued for 20 min, and the aqueous phasewas extracted with DCM. The combined organic phase was washed withsaturated brine, dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum to give benzyl (3,3-difluorocyclopentyl)carbamate(yield: 62%) as a white solid. SFC separation of the mixture viaOD-3S_4_5%-40%_3ML Column: Chiralcel OD-3 100×4.6 mm I.D., 3 μm Mobilephase: iso-propanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3mL/min Wavelength: 220 nm) gave (R)-benzyl(3,3-difluorocyclopentyl)carbamate and (S)-benzyl(3,3-difluorocyclopentyl)carbamate. ¹H NMR (400 MHz, CDCl₃) δ ppm:67.40-7.33 (m, 5H), 5.14-5.10 (m, 2H), 4.93 (s, 1H), 4.27-4.22 (m, 1H),2.51 (qd, J=14.26, 8.28 Hz, 1H), 2.24-2.01(m, 4H) 1.71-1.70 (m, 1H). MS(ESI) m/z=256.3 [M+H]⁺.

(R)-3,3-Difluorocyclopentanamine. To a solution of (R)-benzyl(3,3-difluorocyclopentyl)carbamate (1 equiv.) in MeOH (0.15 M) was addedPd/C (0.1 equiv., 10% Pd by wt.) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (20 psi) at room temperature for 18 h. The reaction mixture wasfiltered and the filtrate was concentrated in vacuum to give(R)-3,3-difluorocyclopentanamine (57%) as a yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 3.37-3.30 (m, 1H), 3.16 (s, 2H), 2.35-2.20 (m, 2H),1.93-1.89 (m, 3H), 1.46-1.41 (m, 1H).

cis-4-((2-4(R)-3,3-Difluorocyclopentyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamide.To a mixture of (R)-3,3-difluorocyclopentanamine (1.00 equiv.) andcis-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamide(1.50 equiv.) (prepared as described herein) in DMF (0.5 M) was addedDIEA (2 equiv.) in one portion at room temperature. The mixture wasstirred at room temperature for 18 h. The mixture was purified byprep-HPLC to affordcis-4424(R)-3,3-difluorocyclopentyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamide(60%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 9.02-8.96 (m,1H), 8.69-8.48 (m, 1H), 5.90 (d, J=5.65 Hz, 1H), 5.49 (s, 2H), 4.45-4.28(m, 2H), 2.64 (qd, J=13.85, 8.03 Hz, 1H), 2.29-2.39 (m, 5H), 1.96-1.84(m, 9H). MS (ESI) m/z=385.1 [M+H]⁺.

cis-4-((5-Amino-2-4(R)-3,3-difluorocyclopentyl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide.To a solution ofcis-4424(R)-3,3-difluorocyclopentyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexanecarboxamide(1.00 equiv.) in MeOH (0.02 M) was added Pd/C (0.1 equiv., 10% Pd bywt.) under N₂. The suspension was degassed under vacuum and purged withH₂ several times. The mixture was stirred under H₂ (20 psi) at roomtemperature for 18 h. The reaction mixture was filtered and the filtratewas concentrated in vacuum to givecis-4-((5-amino-2-(((R)-3,3-difluorocyclopentyl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(94%) as a violet solid. MS (ESI) m/z=355.2 [M+H]⁺.

cis-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-(((R)-3,3-difluorocyclopentyl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a mixture ofcis-4-((5-amino-2-(((R)-3,3-difluorocyclopentyl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(1 equiv.) in DMF (0.35 M) was added1,5-dichloro-3-fluoro-2-isothiocyanatobenzene (1 equiv., prepared asdescribed herein). The mixture was stirred at room temperature for 1.5h. To the mixture was added DIC (2 equiv.), and the mixture was stirredat room temperature for 18 h. Standard work-up and purification affordedcis-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((R)-3,3-difluorocyclopentyl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(30%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.01 (s, 1H), 7.62-7.24 (m,2H), 4.54-4.52(m, 2H), 2.89-2.65 (m, 2H), 2.71-2.62 (m, 2H), 2.35-2.24(m, 5H), 2.11-2. 04 (m, 1H), 1.81-1.74(m, 5H). MS (ESI) m/z=542.1[M+H]⁺.

Example 41(1S,4s)-4-(8-((2,6-Dichloro-4-cyanophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

3-Methyltetrahydropyran-4-one. To a cooled (0° C.) solution of DIA (1.1equiv.) in of anhydrous THF (0.6 M) was added n-BuLi (1.2 equiv., 2.5 Min hexane) dropwise over 40 min. After the addition, the mixture wasstirred for 30 min at 0° C. and then cooled to −78° C. A solution oftetrahydropyran-4-one (1 equiv.) and HMPA (1 equiv.) in THF (6 M) wasadded dropwise over 2 h. Methyliodide (3 equiv.) was added dropwise at−78° C. The reaction mixture was stirred overnight at room temperature,then quenched by addition of citric acid and extracted with ethylacetate. The combined organic layer was dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified via silica gelchromatography to give 3-methyltetrahydropyran-4-one as a yellow oil(15%).

¹H NMR (400 MHz, CDCl₃) δ ppm: 4.30-4.23 (m, 1H), 4.22-4.15 (m, 1H),3.73 (dt, J=3.1, 11.5 Hz, 1H), 3.34 (t, J=10.9 Hz, 1H), 2.74-2.61 (m,2H), 2.41 (td, J=2.7, 14.1 Hz, 1H), 1.01 (d, J=6.7 Hz, 3H).

trans-N-Benzyl-3-methyltetrahydro-2H-pyran-4-amine 4 trans andcis-N-benzyl-3-methyltetrahydro-2H-pyran-4-amine. To a mixture of3-methyltetrahydropyran-4-one (1.1 equiv.) and phenylmethanamine (1equiv.) in MeOH (0.9 M) were added acetic acid (1 equiv.) and NaBH₃CN(1.5 equiv.) at 0° C. The reaction mixture was stirred at roomtemperature overnight. The solvent was removed in vacuum and partitionedbetween DCM and aqueous potassium carbonate. The separated organic phasewas dried over Na₂SO₄ and concentrated. The residue was purified byprep-HPLC to give trans-N-benzyl-3-methyltetrahydro-2H-pyran-4-amine(12%) and cis-N-benzyl-3-methyltetrahydro-2H-pyran-4-amine as a whitesolid (13%). trans-¹H NMR (400 MHz, CDCl₃) δ ppm: 7.46-7.41 (m, 2H),7.37 (t, J=7.3 Hz, 2H), 7.33-7.27 (m, 1H), 4.03-4.0 (m, 2H), 3.86 (dd,J=4.6, 11.5 Hz, 1H), 3.82-3.78 (m, 1H), 3.38 (dt, J=2.2, 11.8 Hz, 1H),3.01 (t, J=11.0 Hz, 1H), 2.40 (dt, J=4.1, 10.3 Hz, 1H), 2.01 (tdd,J=2.1, 4.2, 13.0 Hz, 1H), 1.82-1.67 (m, 1H), 1.66-1.53 (m, 1H), 0.96 (d,J=6.5 Hz, 3H). cis-¹H NMR (400 MHz, MeOH-d₄) δ ppm: 7.40-7.31 (m, 4H),7.29-7.23 (m, 1H), 3.92 (td, J=3.4, 11.4 Hz, 1H), 3.82-3.74 (m, 2H),3.72 (dd, J=2.4, 9.0 Hz, 1H), 3.49 (dd, J=2.5, 11.4 Hz, 1H), 3.40 (dt,J=3.0, 11.4 Hz, 1H), 2.85 (td, J=4.3, 10.8 Hz, 1H), 1.98 (dq, J=4.0, 6.7Hz, 1H), 1.75-1.63 (m, 1H), 1.05 (d, J=7.2 Hz, 3H).

(3R,4S)-N-Benzyl-3-methyltetrahydro-2H-pyran-4-amine and(3S,4R)-N-benzyl-3-methyltetrahydro-2H-pyran-4-amine.Trans-N-benzyl-3-methyltetrahydro-2H-pyran-4-amine 5A trans (2.6 g 12.6mmol) was separated by chiral-HPLC (AD-3S_3_5_40_3ML Column: ChiralpakAD-3 100×4.6 mm I.D., 3 um Mobile phase: MeOH (0.05% DEA) in CO₂ from 5%to 40% Flow rate: 3 mL/min Wavelength: 220 nm) to afford(3R,4S)-N-benzyl-3-methyltetrahydro-2H-pyran-4-amine as a colorless oiland (3S,4R)-N-benzyl-3-methyltetrahydro-2H-pyran-4-amine as a whitesolid.

(3S,4R)-3-Methyltetrahydro-2H-pyran-4-amine hydrochloride. To a solutionof (3S,4R)-N-benzyl-3-methyltetrahydro-2H-pyran-4-amine (1 equiv.) inanhydrous MeOH (0.12 M) was added Pd/C (0.1 equiv., 10% Pd/C by wt.)under N₂ atmosphere. The suspension was degassed under vacuum and purgedwith hydrogen several times. The reaction mixture was stirred underhydrogen balloon for 3 h at room temperature. The reaction was filteredthrough a pad of celite and washed with MeOH. The filtrate was treatedwith 4 M HCl/MeOH and concentrated to afford(3S,4R)-3-methyltetrahydro-2H-pyran-4-amine hydrochloride as a whitesolid (86%).

(1S,4s)-4-((2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) (prepared as described herein) in anhydrous DMF (0.5 M) wereadded (3S,4R)-3-methyltetrahydro-2H-pyran-4-amine hydrochloride (1equiv.) and DIEA (3 equiv.). The reaction solution was diluted withbrine. The formed precipitated solid was collected by filtration to give(1S,4s)-4-((2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(63%).

(1S,4s)-4-((5-Amino-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide.To a solution of(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) in MeOH (0.1 M) was added Pd/C (0.1 equiv, 10% Pd by wt.)under nitrogen atmosphere. The suspension was degassed under vacuum andpurged with hydrogen several times. The reaction mixture was stirredunder hydrogen balloon for 16 h at room temperature. The reaction wasfiltered through a pad of celite and washed with MeOH. The filtrate wasconcentrated in vacuum to afford(1S,4s)-4-((5-Amino-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(82%). ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.51 (s, 1H), 5.58-5.28 (m, 3H),4.38 (d, J=8.92 Hz, 1H), 4.14 (s, 1H), 4.02-3.93 (m, 1H), 3.89 (dd,J=11.54, 4.38 Hz, 1H), 3.69-3.56 (m, 1H), 3.55-3.42 (m, 1H), 3.12 (t,J=11.12 Hz, 1H), 2.48 (s, 2H), 2.33 (td, J=8.30, 3.94 Hz, 1H), 2.12-2.00(m, 1H), 1.94-1.70 (m, 8H), 1.45 (qd, J=12.02, 4.58 Hz, 1H), 0.90 (d,J=6.68 Hz, 3H).

(1S,4s)-4-(8-((2,6-Dichloro-4-cyanophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution of(1S,4s)-4-((5-Amino-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) in anhydrous DMF (0.17 M) was added3,5-dichloro-4-isothiocyanatobenzonitrile (1 equiv.) (prepared asdescribed herein). The reaction was stirred for 90 min at roomtemperature. Then DIC (2 equiv.) was added and stirring was continued atroom temperature overnight. Standard work-up and purification methodsafforded(1S,4s)-4-(8-((2,6-dichloro-4-cyanophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(59%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.82 (s, 2H), 7.58 (s, 1H),4.63-4.41 (m, 1H), 3.99 (dd, J=11.42, 4.02 Hz, 1H), 3.91 (dd, J=11.48,4.32 Hz, 1H), 3.84-3.61 (m, 2H), 3.32-3.22 (m, 1H), 2.86 (d, J=12.56 Hz,2H), 2.66 (s, 1H), 2.35 (d, J=13.04 Hz, 2H), 2.07-1.95 (m, 1H),1.87-1.65 (m, 5H), 1.54 (qd, J=12.16, 4.52 Hz, 1H), 0.93 (d, J=6.64 Hz,3H). MS (ESI) m/z=544 [M+H]⁺.

Example 42(1S,4s)-1-Methyl-4-(2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

Ethyl(1S,4s)-1-methyl-4-(2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylate.To a mixture of ethyl(1S,4s)-4-((5-amino-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(1 equiv., prepared as described herein) in DMF (0.35 M) was added1,3,5-trichloro-2-isothiocyanatobenzene (1 equiv.). The mixture wasstirred at 15-20° C. for 1.5 h. DIC (1 equiv.) was added to the reactionin one portion. The mixture was stirred at 15-20° C. for 16 h. Thereaction was diluted with water, extracted with ethyl acetate, driedover Na₂SO₄, filtered and concentrated. The residue was purified withcolumn chromatography (petroleum/Ethyl acetate=5:11:1) to give(1S,4s)-ethyl1-methyl-4-(2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexanecarboxylate(88%) as a yellow solid.

(1S,4s)-1-Methyl-4-(2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylicacid. To a solution of (1S,4s)-ethyl1-methyl-4-(2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexanecarboxylate(1 equiv.) in MeOH/water (4/1, 0.1 M) was added NaOH (6 equiv.). Thereaction was refluxed for 30 h. The reaction was concentrated, dilutedwith water, and extracted with ethyl acetate. The aqueous phase wasacidified with 3M HCl to pH=3-5, extracted with DCM, dried over Na₂SO₄,filtered and concentrated to give(1S,4s)-1-Methyl-4-(2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxylicacid. (53%) as a yellow solid. MS (ESI) m/z=567.1 [M+H]⁺.

(1S,4s)-1-Methyl-4-(2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a mixture ofcis-1-methyl-4-(2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexanecarboxylicacid (1 equiv.) in DMF (0.4 M) was added HATU (1 equiv.), DIEA (2equiv.) and NH₄Cl (3 equiv.) in one portion at room temperature. Themixture was stirred at room temperature for 24 h. Standard work-up andpurification methods afforded(1S,4s)-1-methyl-4-(2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(19%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.99 (s, 1H), 7.61-7.48 (m,2H), 4.51-4.40 (m, 1H), 4.05-3.96 (m, 1H), 3.94-3.90 (m, 1H), 3.80-3.64(m, 2H), 3.32-3.23 (m, 1H), 2.88-2.69 (m, 2H), 2.48-2.33 (m, 2H),2.01-1.98 (m, 1H), 1.84-1.73 (m, 3H), 1.59-1.36 (m, 3H), 1.25 (s, 3H),0.92 (d, J=6.7 Hz, 3H). MS (ESI) m/z=566.2 [M+H]⁺.

Example 43(1S,4s)-4-(2-(((3S,4R)-3-Methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

(1s,4s)-4-(2-(((3S,4R)-3-Methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a mixture of(1S,4s)-4-((5-amino-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(prepared as described herein) (1 equiv.) in DMF (0.2 M) was added1,3,5-trifluoro-2-isothiocyanatobenzene (1.2 equiv.) in one portion. Themixture was stirred at room temperature for 3 h. DIC (2 equiv.) wasadded and stirring was continued at room temperature for 20 h. LCMSshowed the reaction was complete. Standard work-up and purificationmethods afforded(1s,4s)-4-(2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(47%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.00 (s, 1H), 7.07-6.83 (m,2H), 4.38 (s, 1H), 4.02-3.97 (m, 1H), 3.91 (dd, J=4.3, 11.5 Hz, 1H),3.86-3.69 (m, 2H), 3.38-3.34 (m, 1H), 2.92 (d, J=11.4 Hz, 2H), 2.68 (s,1H), 2.35 (d, J=12.5 Hz, 2H), 2.02 (s, 1H), 1.86-1.69 (m, 5H), 1.60-1.48(m, 1H), 0.93 (d, J=6.5 Hz, 3H). MS (ESI) m/z=504.4 [M+H]⁺.

Example 44(1S,4s)-4-(8-((4-Chloro-2,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

(1S,4s)-4-(8-((4-Chloro-2,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide.To a mixture of(1S,4s)-4-((5-amino-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(prepared as described herein (1 equiv.) in DMF (0.09 M) was added5-chloro-1,3-difluoro-2-isothiocyanatobenzene (prepared as describedherein) (1.2 equiv.) in one portion. The mixture was stirred at roomtemperature for 8 h. DIC (2 equiv.) was added and stirring was continuedat room temperature for 20 h. Standard work-up and purification methodsafforded(1S,4s)-4-(8-((4-chloro-2,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexanecarboxamide(44%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.02 (s, 1H), 7.29-7.06 (m,2H), 4.58-4.33 (m, 1H), 3.99 (d, J=7.9 Hz, 1H), 3.91 (dd, J=4.3, 11.5Hz, 1H), 3.85-3.69 (m, 2H), 3.37 (s, 1H), 2.90 (s, 2H), 2.68 (s, 1H),2.35 (d, J=12.5 Hz, 2H), 2.03 (d, J=12.8 Hz, 1H), 1.77 (d, J=11.8 Hz,5H), 1.60-1.48 (m, 1H), 0.93 (d, J=6.7 Hz, 3H). MS (ESI) m/z=520.3[M+H]⁺.

Example 45(1S,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

(1S,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.To a solution(1S,4s)-4-((5-amino-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide(prepared as described herein (1 equiv.) in anhydrous DMF (0.2 M) wasadded 1,5-dichloro-3-fluoro-2-isothiocyanatobenzene (1 equiv., preparedas described herein). The reaction was stirred for 90 min at roomtemperature. DIC (2 equiv.) was added and stirring was continued at roomtemperature overnight. Standard work-up and purification methodsafforded(1S,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(40%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.00 (s, 1H), 7.63-7.20 (m,2H), 4.45 (s, 1H), 3.99 (dd, J=11.36, 4.08 Hz, 1H), 3.91 (dd, J=11.48,4.32 Hz, 1H), 3.86-3.66 (m, 2H), 3.32-3.25 (s, 1H), 3.01-2.77 (s, 2H),2.67 (s, 1H), 2.35 (d, J=13.04 Hz, 2H), 2.02 (d, J=12.80 Hz, 1H),1.88-1.64 (m, 5H), 1.62-1.44 (m, 1H), 0.93 (d, J=6.64 Hz, 3H). MS (ESI)m/z=536.2 [M+H]⁺.

Example 46(1s,4s)-4-(8-((4-Chloro-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

1,4-Dioxaspiro[4.5]decane-8-carbonitrile. To a −10° C. solution of 1,4dioxaspiro[4.5]decan-8-one (1 equiv.), ethanol (1.78 equiv.) andtoluenesulfonylmethyl isocyanide (1.3 equiv.) in DME (0.3 M) was addedpotassium 2-methylpropan-2-olate (2.3 equiv.) portion wise. The reactionwas stirred at −10° C. for 1 h, and 15 h at room temperature. Thereaction mixture was concentrated to a beige solid, dissolved in waterand extracted with ether. The combined extracts were washed with brineand dried. Concentration under reduced pressure gave an orange oil. Thismaterial was purified by distillation [(103° C. (oil bath 150° C.) atabout 2-3 mbar] to give 1,4-dioxaspiro[4.5]decan-8-one as a colorlessoil (87% yield). ¹ H NMR (400 MHz, CDCl₃) δ ppm: 3.88-4.02 (m, 4H),2.56-2.74 (m, 1H), 1.79-2.05 (m, 6H), 1.50-1.71 (m, 2H).

Methyl-4-oxo-cyclohexanecarbonitrile. To a 0° C. solution of1,4-dioxaspiro[4.5]decane-8-carbonitrile (1 equiv.) in THF (0.5 M) wasadded 1 M lithium bis(trimethylsilyl)amide in THF (1.25 equiv.)dropwise. The resulting solution was stirred for 1 h at 0° C. beforeiodomethane (1.5 eq) was added. After 1 h stirring at 0° C., thereaction was stirred at room temperature for 15 h. The reaction mixturewas quenched with saturated aqueous ammonium chloride and extracted withethyl acetate. The organic phases were combined and washed withsaturated aqueous sodium chloride. The organic layer was dried overanhydrous MgSO₄, filtered, and concentrated. The crude product wasstirred with hydrochloric acid (2 equiv.) in acetone (0.3 M) at 25° C.for 5 h. The reaction mixture was cooled to 0° C. and the pH wasadjusted to 8 with 3N sodium hydroxide. The mixture was extracted withether. The organic portions were combined, dried over MgSO₄, andconcentrated. The crude product was purified by silica gel columnchromatography to afford 1-methyl-4-oxo-cyclohexanecarbonitrile as awhite solid (56% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.41-2.48 (m,2H), 2.23-2.34 (m, 2H), 2.09-2.23 (m, 2H), 1.86 (td, J=13.18, 4.49 Hz,2H), 1.37-1.47 (m, 3H). MS (ESI) m/z=138.3 [M+H]⁺.

(1s,4s)-4-(Benzylamino)-1-methylcyclohexanecarbonitrile. To a solutionof 1-methyl-4-oxocyclohexanecarbonitrile (1 equiv.) in MeOH (0.5 M) wasadded phenylmethanamine (3 equiv.). The resulting solution was stirredfor 2 h at room temperature. The solution was cooled to −78° C. andlithium borohydride (2M in THF, 1.1 equiv.) was added dropwise. Thesolution was allowed to slowly warm to room temperature overnight. After12 h, the reaction mixture was quenched with saturated aqueous sodiumbicarbonate and extracted with ethyl acetate. The organic phase wascombined and washed with saturated aqueous sodium bicarbonate. Theorganic layer was dried over MgSO₄, filtered, and concentrated. Thecrude product was purified to afford the title compound((1s,4s)-4-(benzylamino)-1-methylcyclohexanecarbonitrile as a whitesolid (8:1 cis:trans). ¹H NMR (400 MHz, CHCl₃) δ ppm: 7.29-7.40 (m, 4H),7.23-7.28 (m, 1H), 3.83 (s, 2H), 2.46 (tt, J=10.98, 3.66 Hz, 1H),1.95-2.06 (m, 4H), 1.45-1.58 (m, 2H), 1.23-1.40 (m, 5H). MS (ESI)m/z=229.2 [M+H]⁺.

(1s,4s)-4-(Benzylamino)-1-methylcyclohexane-1-carboxamide. To a solutionof (1s,4s)-4-(benzylamino)-1-methylcyclohexanecarbonitrile (1 equiv.) in1,4-dioxane (4.75 M) was added sulfuric acid 95-98% (5 equiv.). Thereaction was stirred at 100° C. for 2 h. The reaction mixture was cooledto room temperature and quenched with saturated aqueous sodiumbicarbonate and adjusted to pH to 8 with sodium carbonate. The solutionwas extracted with DCM/MeOH. The organic phases were combined, andwashed with saturated aqueous sodium bicarbonate. The organic layer wasdried over sodium sulfate, filtered, and concentrated. The crude productwas purified by silica gel column chromatography to afford an 8/1mixture of diastereomers of(1s,4s)-4-(benzylamino)-1-methylcyclohexane-1-carboxamide as a whitesolid (83% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.25-7.35 (m, 4H), 7.14-7.24 (m, 1H),7.08 (s, 1H), 6.77 (s, 1H), 3.69 (s, 2H), 2.24-2.35 (m, 1H), 2.07 (d,J=12.50 Hz, 2H), 1.63-1.75 (m, 2H), 0.92-1.17 (m, 7H). MS (ESI)m/z=247.2 [M+H]⁺.

(1s,4s)-4-Amino-1-methylcyclohexane-1-carboxamide. To a solution of(1s,4s)-4-(benzylamino)-1-methylcyclohexanecarboxamide (1 equiv.) inMeOH (0.5 M) was added Pd/C (0.015 equiv, 10% by wt.). The solution wasstirred under hydrogen (1 atm) at room temperature for 15 h. Thereaction mixture was filtered through celite and concentrated to afford(1s,4s)-4-amino-1-methylcyclohexane-1-carboxamide as a white solid(100%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.07 (br. s., 1H), 6.75 (br.s., 1H), 2.38-2.48 (m, 1H), 1.97-2.13 (m, 2H), 1.45-1.60 (m, 2H),0.96-1.11 (m, 7H). MS (ESI) m/z=157.2 [M+H]⁺.

(1s,4s)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide.To a −78° C. solution of (1s,4s)-4-amino-1-methylcyclohexanecarboxamide(1 equiv), DIEA (1.5 equiv.) in DCM (0.5 M) was added the suspension of2,4-dichloro-5-nitropyrimidine (1.0 equiv.) in THF (1.5 M) dropwise. Thereaction was stirred at −78° C. for 1 h, and allowed to warm up to roomtemperature over 2 h. The reaction was stirred for another h at roomtemperature. The reaction mixture was concentrated. The crude waspurified by silica gel column chromatography. The resulting solid wastriturated several times in ethyl acetate to afford(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamideas yellow solid (65% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.54 (d,J=8.20 Hz, 1H), 7.18 (s, 1H), 6.86 (s, 1H), 3.98-4.15 (m, 1H), 2.16 (d,J=13.28 Hz, 2H), 1.73 (dd, J=12.69, 3.32 Hz, 2H), 1.50-1.65 (m, 2H),1.16-1.28 (m, 2H), 1.06 (s, 3H). MS (ESI) m/z=314.0 [M+H]⁺.

(1s,4s)-1-Methyl-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide.(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1 equiv.) and tetrahydro-2H-pyran-4-amine hydrochloride (1 equiv.) wereslurried in THF (0.06 M) at room temperature. DIEA (4 equiv.) was addedand the reaction was stirred at 50° C. overnight. The reaction mixturevolume was reduced in vacuo and used directly in the next step.

(1s,4s)-4-((5-Amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide.To a MeOH solution (0.05 M) of(1s,4s)-1-methyl-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 equiv.) was added Pd/C (0.1 equiv, 10% Pd by wt.). The reaction wasstirred under 1 atm of H₂ overnight. The reaction was filtered throughcelite and the filtrate was reduced in vacuo to afford(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexanecarboxamide(91% yield). MS (ESI) m/z=349.3[M+1]⁺.

(1s,4s)-4-(8-((4-Chloro-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.To a(1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexanecarboxamide(1 equiv.) solution of DMF (0.15 M) was added5-chloro-1,3-difluoro-2-isothiocyanatobenzene (prepared as describedherein) (1.09 equiv.) to give a yellow solution. The solution wasstirred at room temperature for 1 h. To the reaction mixture was addedEDC (1.09 equiv.) and the mixture was heated at 50° C. for 1.5 h.Standard work-up and purification methods afforded(1s,4s)-4-(8-((4-chloro-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide(38%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.59 (s, 1H) 7.43 (d, J=7.81 Hz,1H) 7.21-7.30 (m, 1H) 7.10-7.21 (m, 1H) 6.67 (d, J=8.20 Hz, 1H) 6.49 (d,J=7.03 Hz, 1H) 4.17-4.44 (m, 1H) 3.71-3.86 (m, 3H) 3.42-3.62 (m, 2H)2.49-2.67 (m, 1H) 2.26 (t, J=12.89 Hz, 2H) 1.72-1.88 (m, 2H) 1.61 (d,J=10.54 Hz, 1H) 1.54 (d, J=10.54 Hz, 1H) 1.33-1.47 (m, 2H) 1.11-1.27 (m,2H) 0.95-1.09 (m, 3H). MS (ESI) m/z=520.2 [M]⁺.

Example 47(1R,4s)-4-(2-(((S)-1-Hydroxypropan-2-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

(1R,4s)-4-((2-(((S)-1-Hydroxypropan-2-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide.(1s,4s)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1 equiv.) and (S)-2-aminopropan-1-ol (1.03 equiv.) were slurried in THF(0.3 M) and DIEA (4 equiv.) was added. The reaction was stirred at 50°C. overnight. The reaction mixture was concentrated and used withoutfurther purification.

(1R,4s)-4-((5-amino-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide.To a solution of(1R,4s)-4-((2-(((S)-1-hydroxypropan-2-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1 equiv.) in MeOH (0.1 M) was added Pd/C (0.1 equiv., 10% Pd by wt.)and the reaction was purged in vauco followed by H₂. The reaction wasstirred at room temperature under H₂. The reaction was filtered throughcelite and concentrated to afford(1R,4s)-4-((5-amino-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(99%). MS (ESI) m/z=323.4[M+1]⁺.

(1R,4s)-4-(2-(((S)-1-Hydroxypropan-2-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.(1R,4s)-4-((5-Amino-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1 equiv.) and 1,3,5-trichloro-2-isothiocyanatobenzene (1.1 equiv.) inDMF (0.15 M) were stirred at room temperature for 1 h. To this reaction,EDC (2 equiv.) was added and the mixture was heated to 50° C. for 1.5 h.Standard work-up and purification methods afforded(1R,4s)-4-(2-(((S)-1-hydroxypropan-2-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide(28%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.51-7.64 (m, 2H), 7.25 (br.s.,1H), 6.81 (s, 1H), 6.12 (d, J=6.31 Hz, 1H), 4.70 (t, J=5.99 Hz, 1H),4.39 (t, J=3.94 Hz, 1H), 3.77-3.93 (m, 1H), 3.42-3.57 (m, 1H), 3.21-3.30(m, 1H), 2.58-2.73 (m, 3H), 2.29 (t, J=10.56 Hz, 1H), 1.63 (br. s., 1H),1.20-1.35 (m, 2H), 1.11-1.19 (m, 2H), 1.09 (s, 2H). MS (ESI) m/z=527[M+H]⁺.

Example 48(1R,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-4(S)-1-hydroxypropan-2-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

(1R,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-(((S)-1-hydroxypropan-2-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.((1R,4s)-4-((5-Amino-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide1 equiv., prepared as disclosed herein) and1,5-dichloro-3-fluoro-2-isothiocyanatobenzene (prepared as describedherein) (1.1 equiv.) were stirred in DMF (0.15 M) for 1 h. EDC (2equiv.) was added to the reaction mixture and stirring was continued at50° C. for 1.5 h. Standard work-up and purification methods afforded(1R,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((S)-1-hydroxypropan-2-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide(22%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm: 7.52-7.64 (m, 1H) 7.36-7.49 (m,1H) 7.26 (br. s., 1H) 6.74-6.93 (m, 1H) 6.12 (br. s., 1H) 4.67-4.81 (m,1H) 4.28-4.49 (m, 1H) 3.86 (dt, J=12.53, 6.50 Hz, 1H) 3.45-3.63 (m, 1H)3.21-3.28 (m, 1H) 2.72 (d, J=17.65 Hz, 1H) 2.56-2.69 (m, 2H) 2.18-2.33(m, 1H) 1.60 (br. s., 2H) 1.19-1.32 (m, 2H) 1.07-1.19 (m, 4H). MS (ESI)m/z=510.2 [M+H]⁺.

Example 49(1R,4s)-4-(8-((2,6-Dichloro-4-cyanophenyl)amino)-2-4(S)-1-hydroxypropan-2-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

(1R,4s)-4-(8-((2,6-Dichloro-4-cyanophenyl)amino)-2-(((S)-1-hydroxypropan-2-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.((1R,4s)-4-((5-Amino-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1 equiv., prepared as disclosed herein) and3,5-dichloro-4-isothiocyanatobenzonitrile (1.1 equiv.) were stirred inDMF (0.15 M). The solution was stirred at room temperature for 1 h. EDC(2 equiv.) was added to the reaction mixture, and the reaction wasstirred at 50° C. for 1.5 h. Standard work-up and purification methodsafforded(1R,45)-4-(8-((2,6-dichloro-4-cyanophenyl)amino)-2-(((S)-1-hydroxypropan-2-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide(6%).

¹H NMR (500 MHz, DMSO-d₆) δ ppm: 8.01 (s, 1H) 7.68 (s, 1H) 7.25 (br. s.,1H) 6.82 (s, 1H) 6.21 (br. s., 1H) 4.71 (t, J=5.99 Hz, 1H) 4.31-4.48 (m,1H) 3.77-3.92 (m, 1H) 3.53 (dt, J=10.40, 4.89 Hz, 1H) 3.20-3.30 (m, 1H)2.53-2.74 (m, 3H) 2.28 (t, J=10.56 Hz, 1H) 1.62 (br. s., 1H) 1.20-1.34(m, 1H) 1.10-1.20 (m, 2H) 1.09 (s, 2H). MS (ESI) m/z=5172 [M+H]⁺.

Example 50(1S,4s)-4-(8-((2,6-Dichloro-4-cyanophenyl)amino)-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

(1S,4s)-4-((2-(((3S,4R)-3-Fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide.To a mixture of(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1.00 equiv.) and (3S,4R)-3-fluorotetrahydro-2H-pyran-4-aminehydrochloride (1.02 equiv.) in DMF (0.3 M) was added DIEA (2.2 equiv.).The mixture was stirred at 30° C. for 16 h. The mixture was diluted withH₂O and extracted with ethyl acetate. The combined organic phase waswashed with saturated brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum to afford(1S,4s)-4-((2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(99% yield) as a yellow solid. The crude product was used withoutfurther purification. MS (ESI) m/z=397.1 [M+H]⁺.

(1S,4s)-4-((5-Amino-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide.To a solution of(1S,4s)-4-((2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1.0 equiv.) in MeOH (0.25 M) was added Pd/C (0.1 equiv, 10% Pd by wt.).The suspension was degassed under vacuum and purged with H₂ severaltimes. The reaction was stirred under H₂ balloon (15 psi) at 30° C. for2 h. The mixture was filtered and concentrated in vacuum to afford(1S,4s)-4-((5-amino-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(90%) as a violet solid. The crude product was used directly in the nextstep without further purification. MS (ESI) m/z=367.2 [M+H]⁺.

(1S,4s)-4-(8-((2,6-Dichloro-4-cyanophenyl)amino)-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.To a solution of(1S,4s)-4-((5-amino-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1 equiv.) in DMF (0.14 M) was added3,5-dichloro-4-isothiocyanatobenzonitrile (1.00 equiv) (prepared asdescribed herein). The mixture was stirred at 30° C. for 2 h. DIC (2equiv.) was added and the mixture was stirred at 30° C. for 16 h. Themixture was diluted with H₂O and extracted with ethyl acetate. Thecombined organic phases were washed with saturated brine, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. Standard work-upand purification methods afforded(1S,4s)-4-(8-((2,6-dichloro-4-cyanophenyl)amino)-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide(64%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.82 (s, 2H), 7.60 (s, 1H),4.62-4.45 (m, 2H), 4.27-4.17 (m, 1H), 4.11-4.05 (m, 1H), 3.93-3.90 (m,1H), 3.74-3.69 (m, 1H), 3.62-3.56 (m, 1H), 2.79-2.73 (m, 2H), 2.41-2.38(m, 2H), 2.23-2.20 (m, 1H), 1.84-1.81 (m, 2H), 1.68-1.61 (m, 1H),1.45-1.39 (m, 2H), 1.25 (s, 3H). MS (ESI) m/z=561.1 [M+H]⁺.

Example 51(1S,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

Ethyl(1S,4s)-1-methyl-4-((2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxylate.To a mixture of ethyl(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(1 equiv.) and (3S,4R)-3-methyltetrahydro-2H-pyran-4-amine hydrochloride(1.05 equiv.) in DMF (0.4 M) was added DIEA (2.3 equiv.) in one portionat room temperature under N₂. The mixture was stirred at roomtemperature for 16 h. The reaction was diluted with water, and extractedwith ethyl acetate. The combined organic layers were dried over Na₂SO₄,filtered and concentrated to give ethyl(1S,4s)-1-methyl-4-((2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxylate(98%). MS (ESI) m/z 422.2 [M+1]⁺.

Ethyl(1S,4s)-4-((5-amino-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate.To a solution of ethyl(1S,4s)-1-methyl-4-((2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxylate(1 equiv.) in MeOH (0.2 M) was added Pd/C (0.1 equiv, 10% Pd by wt.)under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred under H₂ at room temperatureovernight. The reaction mixture was filtered through a pad of celite andthe filtrate was concentrated to give ethyl(1S,4s)-4-((5-amino-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(99%).

Ethyl(1S,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylate.To a mixture of ethyl(1S,4s)-4-((5-amino-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(1 equiv.) in DMF (0.1 M) was added1,5-dichloro-3-fluoro-2-isothiocyanatobenzene (prepared as describedherein) (1 equiv.). The mixture was stirred at 15-20° C. for 1.5 h. DIC(2 equiv.) was added to the reaction in one portion. The mixture wasstirred at room temperature for 16 h. The reaction was diluted withwater, extracted with ethyl acetate, dried over Na₂SO₄, filtered andconcentrated. The resulted residue was purified via columnchromatography to give ethyl(1S,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylate(90%) as a yellow solid.

(1S,4s)-4-(8-((2,4-Dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylicacid. To a solution of ethyl(1S,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylate(1 equiv.) in MeOH/water (0.2M. 4/1) was added NaOH (3 equiv). Thereaction was refluxed for 48 h. The reaction was concentrated, dilutedwith water, and extracted with ethyl acetate. The aqueous phase wasacidified with 3 M HCl to pH=3-5, extracted with DCM, the organic layerwas dried over Na₂SO₄, filtered and concentrated to give(1S,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylicacid (53%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.70(s, 1H), 7.47-7.31 (m, 2H), 4.02-3.75(m, 4H), 3.42-3.37 (m, 1H),2.27-2.61 (m, 1H), 2.45-2.41 (m, 2H), 1.98-1.91 (m, 3H), 1.85-1.81 (m,1H), 1.70-1.60 (m, 1H), 1.51-1.43(m, 2H), 1.29 (s, 3H), 0.94 (d, J=8.0Hz, 3H).

(1S,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.To a mixture of(1S,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexanecarboxylicacid (1 equiv.) in DMF (0.19 M) were added HATU (1.1 equiv.), TEA (1.1equiv.) and NH₄Cl (1.1 equiv.) in one portion at room temperature. Themixture was stirred at room temperature for 24 h. Standard work-up andpurification methods afforded(1S,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide(37%). ¹H NMR (400 MHz, CHCl3) δ ppm: 7.87 (s, 1H), 7.47-7.30 (m, 2H),4.40-4.34 (m, 1H), 4.02-3.98 (m, 1H), 3.94-3.90 (m, 1H), 3.76-3.70 (m,2H), 2.80-2.67 (m, 2H), 2.46-2.34 (m, 2H), 2.03-1.95 (m, 1H), 1.88-1.78(m, 2H), 1.77-1.70 (m, 1H), 1.61-1.41 (m, 3H), 1.25 (s, 3H), 0.92 (d,J=8.0 Hz, 3H). MS (ESI) m/z=550.2 [M+H]⁺.

Example 52(1R,4s)-4-(8-((2-Chloro-4,6-difluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

Ethyl(1R,4s)-4-((2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate.To a mixture of ethyl(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(1 equiv., prepared as described herein) and(3S,4S)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride (1.1 equiv.,prepared as described herein) in DMF (0.1 M) was added DIEA (3 equiv.),and the reaction stirred at room temperature for 16 h. The reaction wasdiluted with water, and extracted with ethyl acetate. The combinedorganic solvents were dried over Na₂SO₄, filtered and concentrated togive ethyl(1R,4s)-4-((2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(96%). MS (ESI) m/z=426.2 [M+H]⁺.

Ethyl(1R,4s)-4-((5-amino-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate.To a solution of ethyl(1R,4s)-4-((2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(1 equiv.) in MeOH (0.2 M) was added Pd/C (0.1 equiv., 10% Pd by wt.)under N₂ atmosphere. The suspension was degassed under vacuum and purgedwith H₂ several times. The reaction was stirred under a H₂ balloon atroom temperature for 16 h. The reaction was filtered through a pad ofcelite and concentrated to give ethyl(1R,4s)-4-((5-amino-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(95%) as a purple solid. MS (ESI) m/z=396.2 [M+H]⁺.

Ethyl(1R,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylate.To a solution of ethyl(1R,4s)-4-((5-amino-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(1 equiv.) in DMF (0.4 M) was added1-chloro-3,5-difluoro-2-isothiocyanatobenzene (1 equiv.). The solutionwas stirred at room temperature for 90 min. DIC (2 equiv.) was added atroom temperature and the reaction mixture was stirred for 18 h. Thereaction was diluted with water, extracted with ethyl acetate, driedover Na₂SO₄, filtered and concentrated. The resulting residue waspurified by column chromatography to give ethyl(1R,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylate(86%) as a yellow solid. MS (ESI) m/z=567.2 [M+H]⁺.

(1R,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylicacid. To a solution of ethyl(1R,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylate(1 equiv.) in MeOH/water (0.1 M, 4/1) was added NaOH (5 equiv). Thereaction was refluxed for 48 h. The reaction was diluted with water, andextracted with ethyl acetate. The aqueous phase was adjusted with 3 MHCl to pH=3-5, extracted with DCM, the organic layer was dried overNa₂SO₄, filtered and concentrated to give(1R,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylicacid (51%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.86(s, 1H), 7.39-6.92 (m, 2H), 4.84-4.71 (m, 1H), 4.58-4.43 (m, 1H),4.41-4.25 (m, 1H), 4.20-4.13 (m, 1H), 4.06-3.77 (m, 3H), 2.74-2.67 (m,2H), 2.46-2.33 (m, 2H), 2.01-1.81 (m, 4H), 1.51-1.44 (m, 2H), 1.30 (s,3H).

(1R,4s)-4-(8-((2-Chloro-4,6-difluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.To a mixture of(1R,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylicacid (1 equiv.) in DMF (0.1 M) was added HATU (1.1 equiv.), TEA (2equiv.) and NH₄Cl (2 equiv.) in one portion at room temperature. Themixture was stirred for 24 h. Standard work-up and purification methods(1R,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide(15%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.92 (s, 1H), 7.29-7.03 (m,2H), 4.85-4.60 (m, 1H), 4.50-4.35 (m, 1H), 4.26-4.11 (m, 2H), 4.07-3.70(m, 3H), 2.85-2.69 (m, 2H), 2.42-2.38 (m, 2H), 2.04-1.91 (m, 1H),1.86-1.84 (m, 3H), 1.55-1.38 (m, 2H), 1.25 (s, 3H). MS (ESI) m/z=538.2[M+H]⁺.

Example 53(1S,4s)-4-(2-(((3S,4R)-3-Fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

(1S,4s)-4-((2-(((3S,4R)-3-Fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide.To a mixture of(1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1 equiv., prepared as described herein) and(3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride (1.02 equiv,prepared as described herein) in DMF (0.3 M) was added DIEA (2.20equiv.), and the mixture was stirred at 30° ° C. for 16 h. The mixturewas diluted with H₂O and extracted with ethyl acetate. The combinedorganic phases were washed with saturated brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuum to afford(1S,4s)-4-((2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(99%). The crude product was used in the next step without furtherpurification. MS (ESI) m/z=397.1 [M+H]⁺.

(1S,4s)-4-((5-Amino-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide.To a solution of(1S,4s)-4-((2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1.0 equiv.) in MeOH (0.1 M) was added Pd/C (0.1 equiv, 10% Pd by wt.).The suspension was degassed under vacuum and purged with H₂ severaltimes. The reaction was stirred under H₂ at room temperature for 2 h.The mixture was filtered and concentrated in vacuum to afford(1S,4s)-4-((5-amino-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(90%). The crude product was used directly in the next step withoutfurther purification. MS (ESI) m/z=367.2 [M+H]⁺.

(1S,4s)-4-(2-(((3S,4R)-3-Fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.To the solution(1S,4s)-4-((5-amino-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxamide(1.0 equiv.) in DMF (0.4 M) was added1,3,5-trichloro-2-isothiocyanatobenzene (1.0 equiv.). The mixture wasstirred at 30° C. for 2 h. DIC (2.0 equiv.) was added and the reactionwas stirred at room temperature for 16 h. The mixture was diluted withH₂O and extracted with ethyl acetate. The combined organic phase waswashed with saturated brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. Standard work-up and purification methodsafforded(1S,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide(40%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 8.02 (s, 1H), 7.56-7.49 (m,2H), 4.63-4.46 (m, 2H), 4.22 (s, 1H), 4.11-4.05 (m, 1H), 3.93-3.90 (m,1H), 3.73 (s, 1H), 3.62-3.60 (m, 1H), 2.76-2.68 (m, 2H), 2.42-2.38 (m,2H), 2.21 (s, 1H), 1.85 (s, 2H), 1.68-1.61 (m, 1H), 1.47-1.41 (m, 2H),1.25 (s, 3H). MS (ESI) m/z=570.1 [M+H]⁺.

Example 54(1S,4s)-4-(8-((2-Chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide

(1S,4s)-Ethyl4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexanecarboxylate.To a mixture of ethyl(1S,4s)-4-((5-amino-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclohexane-1-carboxylate(1 equiv., prepared as described herein) in DMF (0.03 M) was added1-chloro-3,5-difluoro-2-isothiocyanatobenzene (1 equiv.). The mixturewas stirred at room temperature for 1.5 h. DIC (2 equiv.) was added tothe reaction in one portion. The mixture was stirred at room temperaturefor 16 h. The reaction was diluted with water, extracted with ethylacetate, dried over Na₂SO₄, filtered and concentrated. The resultingresidue was purified via column chromatography to give ethyl(1S,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylate(97%) as a yellow solid. MS (ESI) m/z=563.3 [M+H]⁺.

(1S,4s)-4-(8-((2-Chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylicacid. To a solution of ethyl(1S,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylate(1 equiv.) in MeOH/water (0.1 M, 4/1) was added NaOH (5 equiv.). Thereaction was refluxed for 48 h. The reaction was diluted with water, andextracted with ethyl acetate. The aqueous phase was adjusted with 3 MHCl to pH=3-5, extracted with DCM, the organic layer was dried overNa₂SO₄, filtered and concentrated to give(1S,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylicacid (51%) as a yellow solid.

(1S,4s)-4-(8-((2-Chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.To a solution of(1S,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxylicacid (1 equiv.) in DMF (0.3 M) were added HATU (1.2 equiv.), TEA (3equiv.) and NH₄Cl (3 equiv.) in one portion at room temperature. Thereaction was stirred at room temperature for 24 h. Standard work-up andpurification methods afforded(1S,4s)-4-(8-((2-chloro-4,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide(15%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm: 7.98 (s, 1H), 7.34-6.80 (m,2H), 4.38-4.35 (m, 1H), 4.05-3.89 (m, 2H), 3.71-3.65 (m, 2H), 3.28-3.25(m, 1H), 2.88-2.75 (m, 2H), 2.462.42 (m, 2H), 2.08-1.96 (m, 1H),1.95-1.64 (m, 3H), 1.61-1.44 (m, 1H), 1.43-1.32 (m, 2H), 1.23 (s, 3H),0.91 (d, J=6.7 Hz, 3H). MS (ESI) m/z=534.2 [M+H]⁺.

Assays Cell Assays

Determination of the Growth Inhibitory Effect of Aminopurine Compounds.The Lox-IMVI melanoma cell line (Source: NCI-DCTD, catalog No. 0507283)was maintained and tested in RPMI+10% FBS. The seeding density for thecell line was optimized to ensure assay linearity in 384-well plates.

Increasing concentrations of Aminopurine Compound (0.5 nM to 10 μM) werespotted in a 10-point serial dilution fashion (3-fold dilution) induplicate within the plate via an acoustic dispenser (EDC ATS-100) intoan empty 384-well plate. The dimethyl sulfoxide (DMSO) concentration waskept constant for a final assay concentration of 0.2% DMSO. Prior totesting, cells were grown and expanded in culture flasks to providesufficient amounts of starting material. Cells were then diluted totheir desired densities and added directly to the compound-spotted384-well plates. Cells were allowed to grow for 72 hours in 5% CO₂ at37° C. At the time when exposure of cells to compound began (to),initial cell number was assessed via a viability assay (Cell Titer-Glo)by quantifying the level of luminescence generated byadenosine-5′-triphosphate (ATP) present in viable cells. After 72 hours,cell viability of compound-treated cells was assessed via Cell Titer-GloLuminescent Cell Viability Assay (Promega Corporation, Madison, Wis.)and read for luminescence.

All data was normalized and represented as a percentage of theDMSO-treated control cells after 72 h. Results were expressed as a IC₅₀value, which is the compound concentration required to inhibit 50% ofthe untreated control cells during the 72 hours of treatment.

A Four Parameter Logistic Model (Sigmoidal Dose-Response Model) was usedto determine the compound's IC₅₀.

y=(A+((B−A)/(1+((C/x)̂D))))

wherein:

-   -   A=Y_(Min)    -   B=Y_(Max)    -   C=EC₅₀    -   D=Hill Slope    -   IC₅₀ is the compound concentration when Y=50% of DMSO control    -   Y=Luminescence unit

All inhibition curves were processed and evaluated using XLFit andActivity Base (IDBS).

Animal Models

Xenograft model. For xenograft model studies human melanoma cancer celllines were injected into SCID (severe combined immunodeficiency) mice.Cancer cell lines were propagated in culture in vitro. Tumor bearinganimals were generated by injecting precisely determined numbers ofcells into mice. Following inoculation of animals, the tumors wereallowed to grow to a certain size prior to randomization. The micebearing xenograft tumors ranging between pre-determined sizes werepooled together and randomized into various treatment groups. A typicalefficacy study design involved administering one or more compounds atvarious dose levels to tumor-bearing mice. Additionally, referencechemotherapeutic agents (positive control) and negative controls weresimilarly administered and maintained. Tumor measurements and bodyweights were taken over the course of the study.

Mice were anesthetized with inhaled isoflurane and then inoculated withLOX-IMVI tumor cells subcutaneously above the right hind leg with 0.1 mLof a single cell suspension in PBS using a sterile 1 mL syringe fittedwith a 26-gauge needle. Following inoculation of the animals, tumorswere allowed to grow to approximately 75-125 mm³ or in some cases250-400 mm³ prior to randomization of the mice. The tumor of each animalwas measured and animals with tumors in the appropriate range wereincluded in the study. Animals from the study pool were then distributedrandomly into various cages and the cages were randomly assigned tovehicle, positive control, or test article groups. All of the mice weretagged with metal ear tags on the right ear. A typical group consistedof 8-10 animals. For a typical xenograft study, SCID mice bearing tumorswere randomized and dosed with compounds ranging from, for example, 100mg/kg to 0.1 mg/kg with different dose scheduling, including, but notlimited to, qd, q2d, q3d, q5d, q7d and bid. The mice were dosed for 1-4weeks. Tumors were measured twice a week using calipers and tumorvolumes were calculated using the formula of W²×L/2.

In this melanoma model, Aminopurine Compounds have, or are expected tohave, an ED₅₀ value of <100 mg/kg, with some compounds having an ED₅₀ of<10 mg/kg and others an ED₅₀ of <1 mg/kg.

Activity Tables

Each of the compounds in Table 1 was tested in one or more of the assaysand was found to have activity therein, with all of the compounds havingan IC₅₀ below 10 μM in the cell-based assay, with some compounds havingan IC₅₀ above 1 μM (activity level A), some an IC₅₀ between 500 nM and 1μM (activity level B), some an IC₅₀ between 250 nM and 500 nM (activitylevel C), and others having an IC₅₀ below 250 nM (activity level D).

TABLE 1 Cmpd No. Structure Name MH+ Activity 1

(1s,4s)-4-(8-(3-chlorophenylamino)-2- (isopropylamino)-9H-purin-9-yl)cyclohexanecarboxamide 428.4 A 2

(1s,4s)-4-(8-(3-chlorophenylamino)-2- (cyclopentylamino)-9H-purin-9-yl)cyclohexanecarboxamide 454.4 A 3

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,4- difluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 456.3 A 4

(1s,4s)-4-(8-(3-chlorophenylamino)-2- (4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 484.2 A 5

(1s,4s)-4-(8-(2,4-difluorophenylamino)-2-(3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 486.5 A 6

(1s,4s)-4-(8-(2,4-difluorophenylamino)- 2-(1-methylcyclobutylamino)-9H-purin-9-yl)cyclohexanecarboxamide 456.5 A 7

(1s,4s)-4-(2-(tert-butylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 462.5 A 8

(1S,4s)-4-(8-(2,4- difluorophenylamino)-2-((3R,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 486.1 A 9

(1s,4s)-4-(2-(4-methyltetrahydro-2H- pyran-4-ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.1 A 10

(1s,4s)-4-(8-(3-chloro-2- fluorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 502.2 A 11

(1s,4s)-4-(2-(tetrahydro-2H-pyran-4- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.2 D 12

(1s,4s)-4-(8-(2,6-difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide472.2 C 13

(1s,4s)-4-(8-(2-fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide454.2 B 14

(1S,4s)-4-(2-((3R,4R)-3- methyltetrahydro-2H-pyran-4- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.3 B 15

(1S,4s)-4-(8-(2,6- difluorophenylamino)-2-((3R,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 486.3 A 16

(1s,4s)-4-(8-(2-chloro-6- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 484.2 A 17

(1s,4s)-4-(8-(2,6- dichlorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 D 18

(1s,4s)-4-(8-(3-chlorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide470.2 A 19

(1s,4s)-4-(8-(2,4-difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide472.2 A 20

(1s,4s)-4-(8-(3,4- dichlorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 A 21

(1s,4s)-4-(8-(5-chloro-2- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488.3 A 22

(1s,4s)-4-(8-(3-chloro-2- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488.1 A 23

(1s,4s)-4-(8-(2,5-difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide472.2 A 24

(1s,4s)-4-(8-(3-chloro-2- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 484.2 A 25

(1s,4s)-4-(2-(tetrahydro-2H-pyran-4- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 538.1 D 26

(1s,4s)-4-(8-(2,3-difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide472.2 A 27

(1s,4s)-4-(8-(2,4- dichlorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 A 28

(1s,4s)-4-(8-(2-chloro-5- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488.1 A 29

(1s,4s)-4-(8-(2-chloro-4- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488.2 A 30

(1s,4s)-4-(8-(2-chloro-4- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 484.4 A 31

(1s,4s)-4-(8-(3-fluoro-2- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 468.4 A 32

(1s,4s)-4-(8-(4-bromo-2- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 532.1 B 33

(1s,4s)-4-(8-(2-fluoro-4- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 468.2 A 34

(1s,4s)-4-(8-(2-chloro-4- (trifluoromethyl)phenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide538.1 A 35

(1s,4s)-4-(8-(2,6-difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H- purin-9-yl)-1-methylcyclohexanecarboxamide 486.2 B 36

(1s,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488.2 C 37

(1s,4s)-4-(8-(4-fluoro-2- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 468.4 A 38

(1s,4s)-4-(2-(tetrahydro-2H-pyran-4- ylamino)-8-(2,3,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.2 B 39

(1s,4s)-1-methyl-4-(2-(tetrahydro-2H- pyran-4-ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 C 40

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.2 D 41

(1s,4s)-4-(2-(cyclobutylamino)-8- (2,4,6-trifluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 460.1 C 42

(1s,4s)-4-(2-(cyclobutylamino)-8-(2,6- difluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 442.1 A 43

(1s,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-(cyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 458.1 B 44

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 474.2C 45

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,6- difluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 456.2 B 46

(1s,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-(cyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 472.2 B 47

(1s,4s)-4-(8-(2,6-difluorophenylamino)- 2-(isopropylamino)-9H-purin-9-yl)cyclohexanecarboxamide 430.2 A 48

(1s,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-(isopropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 446.2 A 49

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.1 D 50

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 D 51

(1s,4s)-4-(2-(cyclobutylamino)-8-(2,6- dichlorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 474.1 B 52

(1s,4s)-4-(8-(2,6- dichlorophenylamino)-2- (isopropylamino)-9H-purin-9-yl)cyclohexanecarboxamide 462.1 A 53

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.1 D 54

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,6- dichlorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 488.2 B 55

(1s,4s)-4-(2-(oxetan-3-ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 462.2A 56

(1s,4s)-4-(8-(2,6- dichlorophenylamino)-2-(oxetan-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 476.1 A 57

(1s,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-(oxetan-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 460.1 A 58

(1s,4s)-4-(2-(tetrahydro-2H-pyran-4- ylamino)-8-(2,4,5-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.2 B 59

(1s,4s)-4-(2-(isopropylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 496.2 B 60

(1s,4s)-4-(8-(4-chloro-2- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488.1 B 61

(1s,4s)-4-(8-(2-chloro-3- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488.2 A 62

(1s,4s)-4-(8-(2,3- dichlorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.1 A 63

(1s,4s)-4-(8-(2-fluoro-6- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 468.2 A 64

(1s,4s)-4-(8-(5-chloro-2,4- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 A 65

(1s,4s)-4-(2-(tetrahydro-2H-pyran-4- ylamino)-8-(2,4,5-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.1 A 66

(1s,4s)-4-(2-(tetrahydro-2H-pyran-4- ylamino)-8-(2,3,4-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.2 B 67

(1s,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 A 68

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 524.1B 69

(1s,4s)-4-(8-(2-chloro-3- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 484.2 A 70

(1s,4s)-4-(8-(4-chloro-2,5- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 B 71

(1s,4s)-4-(8-(4-chloro-2-fluoro-5- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 502.2 A 72

(1s,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 C 73

(1s,4s)-4-(2-(tetrahydro-2H-pyran-4- ylamino)-8-(2,3,4-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 538.1 A 74

(1s,4s)-4-(8-(2-chloro-4-fluoro-6- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 502.2 A 75

(1s,4s)-4-(8-(4-chloro-2-fluoro-6- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 502.2 A 76

(1S,4s)-4-(2-((R)-tetrahydrofuran-3- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 524.2 C 77

(1s,4s)-4-(2-((1r,4r)-4- methoxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 566.2 B 78

(1s,4s)-4-(2-((1r,4r)-4- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.2 A 79

(1s,4s)-4-(8-(3-chloro-6-fluoro-2- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 502.2 A 80

(1s,4s)-4-(8-(2,5-dichloro-4- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.1 B 81

(1s,4s)-4-(8-(2,3-dichloro-4- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522   A 82

(1s,4s)-4-(8-(2,4-dichloro-3- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 A 83

(1s,4s)-4-(8-(2,3-difluoro-4- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 486.3 B 84

(1s,4s)-4-(8-(2-chloro-3-fluoro-4- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 502.2 B 85

(1s,4s)-4-(8-(2,3-dichloro-4- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.2 A 86

(1s,4s)-4-(8-(2,4-difluoro-6- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 486.3 A 87

(1R,4s)-4-(2-((S)-tetrahydrofuran-3- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 525.2 B 88

(1s,4s)-4-(2-(4,4- difluorocyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 572.1 B 89

(1s,4s)-4-(8-(4-chloro-3-fluoro-2- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 502.1 A 90

(1s,4s)-4-(8-(2-chloro-3,6- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.1 C 91

(1s,4s)-4-(8-(2-chloro-6-fluoro-3- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 502.1 A 92

(1s,4s)-4-(2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-8-((2,4,6- trichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide 586   A 93

(1s,4s)-4-(8-(2-chlorophenylamino)-2- (cyclopentylamino)-9H-purin-9-yl)cyclohexanecarboxamide 545.3 A 94

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,4- dichlorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 488.2 A 95

(1s,4s)-4-(8-(4-chloro-2- fluorophenylamino)-2-(cyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 472.3 A 96

(1s,4s)-4-(8-(2,4- dichlorophenylamino)-2- (isopropylamino)-9H-purin-9-yl)cyclohexanecarboxamide 462.2 A 97

(1s,4s)-4-(8-(2-chloro-4- fluorophenylamino)-2-(isopropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 446.2 A 98

(1s,4s)-4-(2-(isopropylamino)-8-(2,3,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 448.2 A 99

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(isopropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 480.1 C 100

(1s,4s)-4-(8-(2-chloro-4,5- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.1 A 101

(1s,4s)-4-(8-(2-chloro-4,5- dimethylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 498.2 A 102

(1s,4s)-4-(8-(4-chloro-2-fluoro-3- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 502.1 A 103

(1s,4s)-4-(8-(2,4-dichloro-6- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.1 A 104

(1s,4s)-4-(8-(2,3-dichloro-6- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 C 105

(1s,4s)-4-(8-(2,4-dichloro-5- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 A 106

(1s,4s)-4-(8-(2,5-difluoro-4- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 486.2 A 107

(1s,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-(1-(pyridin-3-yl)piperidin-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 564.2 A108

(1s,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-(1-phenylpiperidin-4-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 563.2 A109

(1s,4s)-4-(8-(2,4,6- trichlorophenylamino)-2-(2,2,2-trifluoroethylamino)-9H-purin-9- yl)cyclohexanecarboxamide 526.2 A 110

(1s,4s)-4-(2-(cyclobutylmethylamino)- 8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 524.1 B 111

(1S,4s)-4-(2-((R)-tetrahydro-2H-pyran- 3-ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 539   A 112

(1s,4s)-4-(8-(3,4-dichloro-2- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.2 C 113

(1s,4s)-4-(8-(6-chloro-2,3- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.1 B 114

(1s,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-(1-(methylsulfonyl)piperidin-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 565.1 A 115

(1s,4s)-4-(8-(2,6-difluoro-4- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 486.2 B 116

(1s,4s)-4-(8-(2,6-dichloro-4- methylphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.2 A 117

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(cyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 476.2 B 118

(1s,4s)-4-(2-(cyclobutylamino)-8-(2,6- dichloro-4-fluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 492.1 B 119

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(cyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.1 C 120

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(cyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.2 C 121

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,6-dichloro-4-fluorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide506.1 B 122

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,4-dichloro-6-fluorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide506.2 C 123

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(isopropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 480.1 B 124

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(isopropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 464.1 A 125

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(isopropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 464.2 B 126

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((R)-1-hydroxybutan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 510.1 A127

(3R,4S)-tert-butyl 4-(9-((1s,4R)-4- carbamoylcyclohexyl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2- ylamino)-3-fluoropiperidine-1-carboxylate 607.2 A 128

(3R,4S)-tert-butyl 4-(9-((1s,4R)-4- carbamoylcyclohexyl)-8-(2,6-difluorophenylamino)-9H-purin-2- ylamino)-3-fluoropiperidine-1-carboxylate 589.2 A 129

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(cyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 476.2 A 130

(1s,4s)-4-(2-(cyclobutylamino)-8-(2,4- dichloro-6-fluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 492.1 A 131

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((R)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 496.2 A132

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((R)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 480.2 A133

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((R)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 496.1 B134

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((R)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 480.1 A135

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 496.1 D136

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 480.1 B137

(1S,4s)-4-(2-((R)-1-hydroxybutan-2- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 526.1 A 138

(1R,4s)-4-(2-((3R,4S)-3- fluoropiperidin-4-ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 555.1 A 139

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,3- difluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 456.4 A 140

(1s,4s)-4-(8-(3-chloro-2- fluorophenylamino)-2-(cyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 472   A 141

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,3,6-trifluorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 474.1B 142

(1R,4s)-4-(2-((S)-1-methoxypropan-2- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 526.2 A 143

(1R,4s)-4-(2-((S)-1-hydroxybutan-2- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 478.4 A 144

(1R,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-((S)-1-hydroxybutan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 476.1 A145

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((S)-1-hydroxybutan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 510.1 A146

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((S)-1-hydroxybutan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 494.2 B147

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((S)-1-hydroxybutan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 494.1 A148

(1R,4s)-4-(2-((S)-1-hydroxybutan-2- ylamino)-8-(2,3,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 478.2 A 149

(1R,4s)-4-(8-(2,4- dichlorophenylamino)-2-((S)-1-hydroxybutan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 492.1 A150

(1R,4s)-4-(8-(3-chloro-2- fluorophenylamino)-2-((S)-1-hydroxybutan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 476.1 A151

(1R,4s)-4-(2-((S)-1-hydroxybutan-2- ylamino)-8-(2,3,4-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 478.2 A 152

(1S,4s)-4-(2-((R)-2- hydroxypropylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 512.2 A 153

(1R,4s)-4-(8-(2,6- dichlorophenylamino)-2-((S)-1-hydroxybutan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 492.1 A154

(1R,4s)-4-(2-((S)-1-hydroxybutan-2- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 526   A 155

(3R,4S)-tert-butyl 4-(9-((1s,4R)-4-carbamoylcyclohexyl)-8-(4-chloro-2,6- difluorophenylamino)-9H-purin-2-ylamino)-3-fluoropiperidine-1- carboxylate 623.2 A 156

(1s,4s)-4-(8-((4-chloro-2,6- difluorophenyl)amino)-2-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide 554.1 A 157

(1s,4s)-4-(8-((2,4-dichloro-6- fluorophenyl)amino)-2-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide 570.1 A 158

(R)-tert-butyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 589.2A 159

(R)-tert-butyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-difluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 571.2A 160

(R)-tert-butyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-dichlorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 603.2A 161

(R)-tert-butyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2-chloro-4,6-difluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 605.3A 162

(R)-tert-butyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(4-chloro-2,6-difluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 605.2A 163

(R)-tert-butyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4,6-trichlorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 637.2A 164

(1R,4s)-4-(2-((S)-1-hydroxypropan-2- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 464.1 A 165

(1R,4s)-4-(2-((S)-1-hydroxypropan-2- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 512.1 C 166

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 496.1 B167

(1R,4s)-4-(8-(2,6- difluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 446.1 A168

(1R,4s)-4-(8-(2,6- dichlorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 479.1 A169

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 480.1 B170

(1R,4s)-4-(8-(2,4- dichlorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 478   A171

(1R,4s)-4-(8-(5-chloro-2- fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 462.1 A172

(1R,4s)-4-(8-(3-chloro-2- fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 462.1 A173

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6-ylamino)-8-(2,6-difluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 484.5 A 174

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6-ylamino)-8-(2,6-dichlorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 516.2 A 175

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6- ylamino)-8-(2-chloro-4,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.4 B 176

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6- ylamino)-8-(4-chloro-2,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.1 A 177

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 550   C 178

(1s,4s)-4-(2-(4-hydroxytetrahydrofuran- 3-ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 492   A 179

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide508   A 180

(1s,4s)-4-(8-(2,6- dichlorophenylamino)-2-(4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide506.1 A 181

(1s,4s)-4-(2-(4-hydroxytetrahydrofuran- 3-ylamino-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 540   B 182

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide524.1 A 183

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide524.1 A 184

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide508   A 185

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 540.2 D186

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 556.1 D187

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((R)-tetrahydro-2H-pyran-3-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide506.1 A 188

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((R)-tetrahydro-2H-pyran-3-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide506.2 A 189

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((R)-tetrahydro-2H-pyran-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 A 190

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((R)-tetrahydro-2H-pyran-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 A 191

(1s,4s)-4-(8-(2,4- dichlorophenylamino)-2-(4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide506.2 A 192

(1s,4s)-4-(8-(3-chloro-2- fluorophenylamino)-2-(4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide490.1 A 193

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6- ylamino)-8-(2,6-dichloro-4-fluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 534.1 A 194

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6- ylamino)-8-(4-chloro-2,3-difluoiophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.1 A 195

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6- ylamino)-8-(2,4-dichloro-6-fluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 534   C 196

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6- ylamino)-8-(3-chloro-2,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.2 A 197

(1s,4s)-4-(2-(1-acetylpiperidin-4- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 579.2 A 198

(1s,4s)-4-(2-(1-acetylpiperidin-4- ylamino)-8-(2,4-dichloro-6-fluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 563.2 A 199

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((R)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 492.4 B200

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 540.1 C201

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 556.2 C202

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((S)-tetrahydro-2H-pyran-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 A 203

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((S)-tetrahydro-2H-pyran-3-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide506.1 A 204

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((S)-tetrahydro-2H-pyran-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 A 205

(1s,4s)-4-(2-((1- (hydroxymethyl)cyclopropyl)methyl-amino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 538.2 A 206

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1-(hydroxymethyl)cyclopropyl) methylamino)-9H-purin-9-yl)cyclohexanecarboxamide 522.2 A 207

(1S,4s)-4-(2-((1R,3R)-3- hydroxycyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490   A 208

(1S,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488.4 A209

(1S,4s)-4-(8-(2,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 472.2 A210

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.1 A211

(1S,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 A212

(1S,4s)-4-(2-((1R,3R)-3- hydroxycyclopentylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 538.1 C 213

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 C214

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 A215

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.1 C216

(1S,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 A217

(1S,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 A218

(1S,4s)-4-(2-((1R,3R)-3- hydroxycyclopentylamino)-8-(2,3,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.2 A 219

(1S,4s)-4-(8-(2,4- dichlorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.1 A220

(1S,4s)-4-(2-((1R,3R)-3- hydroxycyclopentylamino)-8-(2,3,4-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.2 A 221

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((R)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 492.1 B222

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((R)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 508   B223

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((R)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 508.1 C224

(1s,4s)-4-(2-(3,3- difluorocyclobutylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 544.1 A 225

(1s,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 494.1 A226

(1s,4s)-4-(2-(3,3- difluorocyclobutylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 496.1 A 227

(1s,4s)-4-(2-(3,3- difluorocyclobutylamino)-8-(2,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 478.2 A 228

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 512.1 B229

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 512.1 A230

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 528.1 C231

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 528.1 A232

(1s,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 512.1 A233

(1s,4s)-4-(2-(3,3- difluorocyclobutylamino)-8-(2,3,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 496.1 B 234

(1s,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 512.1 A235

(1s,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 B236

(1s,4s)-4-(8-(2,6- dichlorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 538.1 C237

(1s,4s)-4-(8-(3-chloro-2- fluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 A238

(1s,4s)-4-(8-(4-chloro-2,5- difluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 540.2 A239

(1s,4s)-4-(2-(4,4- difluorocyclohexylamino)-8-(2,3,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 524.1 B 240

(1s,4s)-4-(8-(2,4- dichlorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 538.2 A241

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((S)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 492.1 A242

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((S)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 492.1 B243

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((S)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 508.1 B244

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((S)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 508.1 B245

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((S)-tetrahydro-2H-pyran-3-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide506.1 A 246

(1R,4s)-4-(2-((3R,4S)-3- fluorotetrahydro-2H-pyran-4-ylamino)-8-(2,4,6-trichlorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide556.1 B 247

(1R,4s)-4-(8-(2,6- difluorophenylamino)-2-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 490.2 A 248

(1s,4s)-4-(8-(2-chloro-4- cyanophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 495.2 B 249

(1S,4s)-4-(2-((1R,2R)-2- hydroxycyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490   A 250

(1S,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488   A251

(1S,4s)-4-(8-(2,6- difluorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 472   A252

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.3 A253

(1S,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 503.3 A254

(1S,4s)-4-(2-((1R,2R)-2- hydroxycyclopentylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 540   B 255

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.2 A256

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.1 A257

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 B258

(1S,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.1 A259

(1S,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 A260

(1S,4s)-4-(2-((1R,2R)-2- hydroxycyclopentylamino)-8-(2,3,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.2 A 261

(1S,4s)-4-(8-(2,4- dichlorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.1 A262

(1S,4s)-4-(8-(5-chloro-2- fluorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488.1 A263

(1S,4s)-4-(8-(3-chloro-2- fluorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488.1 A264

(1S,4s)-4-(2-((1R,2R)-2- hydroxycyclopentylamino)-8-(2,3,4-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.2 A 265

(1S,4s)-4-(8-(4-chloro-2,5- difluorophenylamino)-2-((1R,2R)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.1 A266

(1R,4s)-4-(2-((1S,2S)-2- hydroxycyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.3 A 267

(1R,4s)-4-(8-(2,6- difluorophenylamino)-2-((1S,2S)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 472.2 A268

(1R,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1S,2S)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 A269

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1S,2S)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 A270

(1R,4s)-4-(2-((1S,2S)-2- hydroxycyclopentylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 A 271

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1S,2S)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.2 B272

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1S,2S)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 522.2 A273

(1R,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-((1S,2S)-2-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 A274

(1S,4s)-4-(2-((3S,4R)-3- fluorotetrahydro-2H-pyran-4-ylamino)-8-(2,4,6-trichlorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide556.5 D 275

(1S,4s)-4-(8-(2,6- difluorophenylamino)-2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 490.2 C 276

(1S,4s)-4-(2-((3S,4R)-3- fluorotetrahydro-2H-pyran-4-ylamino)-8-(2,4,6-trifluorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide508.2 D 277

(1R,4s)-4-(2-((3R,4S)-3- fluorotetrahydro-2H-pyran-4-ylamino)-8-(2,4,6-trifluorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide508.2 A 278

(1s,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 529.1 D 279

(1s,4s)-4-(2-((1r,3r)-3- hydroxycyclobutylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 476.1 A 280

(1s,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1r,3r)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490   A281

(1s,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-((1r,3r)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 474.1 A282

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1r,3r)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 492.1 A283

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1r,3r)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 492.1 A284

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1r,3r)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 508.1 A285

(1s,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-((1r,3r)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 492.1 A286

(1s,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-((1r,3r)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 492.1 A287

(1s,4s)-4-(8-(3-chloro-2,5- difluorophenylamino)-2-((1r,3r)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 492.1 A288

(1s,4s)-4-(2-(4,4- difluorocyclohexylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 524.1 C 289

(1s,4s)-4-(2-(4,4- difluorocyclohexylamino)-8-(2,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.1 A 290

(1s,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 B291

(1s,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 540.2 B292

(1s,4s)-4-(2-(1- (methylsulfonyl)piperidin-4-ylamino)-8-(2,4,6-trichlorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide617.1 B 293

(1s,4s)-4-(8-(2,6- dichlorophenylamino)-2-(1-(methylsulfonyl)piperidin-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 581.1 A 294

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(1-(methylsulfonyl)piperidin-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 583.2 A 295

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(1-(methylsulfonyl)piperidin-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 583.2 A 296

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(1-(methylsulfonyl)piperidin-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 599.1 B 297

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(1-(methylsulfonyl)piperidin-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 599.1 A 298

(1s,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-(1-(methylsulfonyl)piperidin-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 583.2 A 299

(1s,4s)-4-(8-(2,4- dichlorophenylamino)-2-(1-(methylsulfonyl)piperidin-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 581.1 A 300

(1s,4s)-4-(2-((1r,3r)-3- hydroxycyclobutylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 524.2 B 301

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1r,3r)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 508.1 B302

(1S,4s)-4-(2-((3R,4R)-3- fluorotetrahydro-2H-pyran-4-ylamino)-8-(2,4,6-trichlorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide556.1 B 303

(1R,4s)-4-(2-((3S,4S)-3- fluorotetrahydro-2H-pyran-4-ylamino)-8-(2,4,6-trichlorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide556.2 D 304

(1S,4s)-4-(8-(2,6- difluorophenylamino)-2-((3R,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 490.2 A 305

(1R,4s)-4-(8-(2,6- difluorophenylamino)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 490.2 B 306

(1R,4s)-4-(2-((3S,4S)-3- fluorotetrahydro-2H-pyran-4-ylamino)-8-(2,4,6-trifluorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide508.2 C 307

(1S,4s)-4-(2-((3R,4R)-3- fluorotetrahydro-2H-pyran-4-ylamino)-8-(2,4,6-trifluorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide508.2 A 308

(1s,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 513.2 D 309

(1s,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 497.2 D 310

(1s,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-((1s,3s)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 494.1 A311

(1R,4s)-4-(2-((3S,4R)-4- hydroxytetrahydrofuran-3-ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 492.3A 312

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((3S,4R)-4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide508.2 A 313

(1R,4s)-4-(2-((3S,4R)-4- hydroxytetrahydrofuran-3-ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 540  B 314

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((3R,4S)-4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide524.1 A 315

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((3R,4S)-4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide524.1 A 316

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((3R,4S)-4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide508.1 A 317

(1R,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-((3S,4R)-4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide508   B 318

(1R,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-((3S,4R)-4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide508   A 319

(1R,4s)-4-(8-(2,4- dichlorophenylamino)-2-((3S,4R)-4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide506.1 A 320

(1R,4s)-4-(8-(5-chloro-2- fluorophenylamino)-2-((3S,4R)-4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide490   A 321

(1S,4s)-4-(8-(4-chloro-2,5- difluorophenylamino)-2-((3R,4S)-4-hydroxytetrahydrofuran-3-ylamino)- 9H-purin-9-yl)cyclohexanecarboxamide508   A 322

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1s,3s)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 492.2 A323

(1s,4s)-4-(2-((1s,3s)-3- hydroxycyclobutylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 524.2 A 324

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1s,3s)-3-hydroxycyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 508   A325

(1R,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-((1S,3S)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 488.2 A326

(1R,4s)-4-(8-(2,6- difluorophenylamino)-2-((1S,3S)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 472.2 A327

(1R,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1S,3S)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.1 B328

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,3S)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 A329

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1S,3S)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 506.2 B330

(1R,4s)-4-(2-((1S,3S)-3- hydroxycyclopentylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 538.1 B 331

(1R,4s)-4-(2-((1S,3S)-3- hydroxycyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.2 A 332

(1S,4s)-4-(2-((1R,3S)-3- hydroxycyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 490.2 A 333

(1S,4s)-4-(2-((1R,3S)-3- hydroxycyclopentylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 538.1 B 334

(1R,4s)-4-(2-(sec-butylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 462.1 B 335

(1R,4s)-4-(2-(sec-butylamino)-8-(2,6- difluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 444.2 A 336

(1R,4s)-4-(2-(sec-butylamino)-8-(2,6- dichlorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 476.1 A 337

(1R,4s)-4-(2-(sec-butylamino)-8-(2-chloro-6-fluorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 460.2A 338

(1R,4s)-4-(2-(sec-butylamino)-8-(2- chloro-4,6-difluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 478   B 339

(1R,4s)-4-(2-(sec-butylamino)-8-(2,4- dichloro-6-fluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 494.1 B 340

(1R,4s)-4-(2-(sec-butylamino)-8-(3- chloro-2,6-difluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 478 A 341

(1S,4s)-4-(2-((1R,3R,4R)-3-hydroxy-4- methylcyclohexylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518 A 342

(1S,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide516.2 A 343

(1S,4s)-4-(8-(2,6- difluorophenylamino)-2-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide500 A 344

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide534 A 345

(1S,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide533.2 A 346

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide550.2 C 347

(1S,4s)-4-(2-((1R,3S)-3- hydroxycyclohexylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 A 348

(1S,4s)-4-(8-(2,6- difluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 486.2 A349

(1S,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.1 A350

(1S,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 502.2 B351

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A352

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 B353

(1S,4s)-4-(2-((1R,3S)-3- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.1 C 354

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 B355

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide550.2 A 356

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide534.2 A 357

(1S,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide534.3 A 358

(1S,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide534.3 A 359

(1S,4s)-4-(2-((1R,3R,4R)-3-hydroxy-4- methylcyclohexylamino)-8-(2,3,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.3 A 360

(1S,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A361

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 D362

(1S,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.1 A363

(1S,4s)-4-(8-(4-chloro-2,5- difluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A364

(1S,4s)-4-(2-((1R,3S)-3- hydroxycyclohexylamino)-8-(2,3,4-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 A 365

(1s,4s)-4-(8-(2,6-dichloro-4- (trifluoromethoxy)phenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide588.2 D 366

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 503.2 D367

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,6- dichloro-4-cyanophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 513.2 D 368

(1s,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-(cyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 467.3 B 369

(1s,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(cyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 497.3 C 370

(1R,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.2 A371

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A372

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A373

(1R,4s)-4-(2-((1S,3R)-3- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.1 B 374

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 A375

(1R,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A376

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 A377

(1R,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A378

(1s,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 547.3 C379

(1s,4s)-4-(8-(4-cyano-2,3- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 497.3 A 380

(1s,4s)-4-(8-(2,3-difluoro-4- methoxyphenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 502.3 A 381

(1S,4s)-4-(2-((1R,3R)-3-hydroxy-4,4- dimethylcyclohexylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 531.8 A 382

(1S,4s)-4-(8-(2,6- difluorophenylamino)-2-((1R,3R)-3- hydroxy-4,4-dimethylcyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 513.8 A383

(1S,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1R,3R)-3- hydroxy-4,4-dimethylcyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 545.7 A384

(1S,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-((1R,3R)-3- hydroxy-4,4-dimethylcyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 530   A385

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,3R)-3-hydroxy-4,4- dimethylcyclohexylamino)-9H-purin-9-yl)cyclohexanecarboxamide 547.7 A 386

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,3R)-3-hydroxy-4,4- dimethylcyclohexylamino)-9H-purin-9-yl)cyclohexanecarboxamide 547.7 A 387

(1S,4s)-4-(2-((1R,3R)-3-hydroxy-4,4- dimethylcyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 579.7 A 388

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1R,3R)-3-hydroxy-4,4- dimethylcyclohexylamino)-9H-purin-9-yl)cyclohexanecarboxamide 563.7 A 389

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,3R)-3-hydroxy-4,4- dimethylcyclohexylamino)-9H-purin-9-yl)cyclohexanecarboxamide 563.7 A 390

(1S,4s)-4-(8-(3-chloro-2,6- difluorophenylamino)-2-((1R,3R)-3-hydroxy-4,4- dimethylcyclohexylamino)-9H-purin-9-yl)cyclohexanecarboxamide 547.7 A 391

(1S,4s)-4-(8-(2,4- dichlorophenylamino)-2-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide532.2 A 392

(1s,4s)-4-(2-(cyclobutylamino)-8-(2,6- dichloro-4-cyanophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 499.2 D 393

(1s,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(cyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 483.2 C 394

(1R,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 471.2 A395

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 487.2 A396

(1s,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 531.3 B397

(1s,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 563.2 D398

(1s,4s)-4-(8-(2-chloro-6-fluoro-4- (trifluoromethyl)phenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide556.2 B 399

(1s,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 535.2 C400

(1s,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 519.2 B401

(1s,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)cyclohexanecarboxamide 503.2 A402

(1R,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-((S)-1-hydroxybutan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 485.3 A403

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 547.3A 404

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-difluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 529.2A 405

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-dichlorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 561.2A 406

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2-chloro-6-fluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 545.2 A407

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2-chloro-4,6-difluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 563.2A 408

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(4-chloro-2,6-difluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 563.2B 409

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4,6-trichlorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 595.2B 410

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-dichloro-4-fluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 579.1A 411

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(4-chloro-2,3-difluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 563.2A 412

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4-dichloro-6-fluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 579.2C 413

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(3-chloro-2,6-difluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 563.3A 414

(R)-methyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,3,4-trifluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 574.2A 415

(1S,4s)-4-(2-((1R,3R)-3- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.1 B 416

(1S,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 502.2 A417

(1S,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.1 A418

(1S,4s)-4-(2-((1R,3R)-3- hydroxycyclohexylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 A 419

(1S,4s)-4-(8-(2,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 486.2 A420

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A421

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.1 A422

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 B423

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536   B424

(1S,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1R,3S)-3-hydroxy-3-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide532.2 A 425

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,3S)-3-hydroxy-3-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide534.2 A 426

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,3S)-3-hydroxy-3-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide534.2 A 427

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,3S)-3-hydroxy-3-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide550.2 B 428

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1R,3S)-3-hydroxy-3-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide550.2 A 429

(1S,4s)-4-(8-(2-chloro-4- fluorophenylamino)-2-((1R,3S)-3-hydroxy-3-methylcyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide516.1 A 430

(1s,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(isopropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 471.2 B 431

(1s,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(isopropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 487.2 B 432

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((S)-1-hydroxybutan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 517.3 B433

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((S)-1-hydroxybutan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 501.2 A434

(1S,4s)-4-(2-((1R,3S)-3- hydroxycycloheptylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 518.2 A 435

(1S,4s)-4-(8-(2,6- dichlorophenylamino)-2-((1R,3S)-3-hydroxycycloheptylamino)-9H-purin-9- yl)cyclohexanecarboxamide 532.2 A436

(1S,4s)-4-(8-(2-chloro-6- fluorophenylamino)-2-((1R,3S)-3-hydroxycycloheptylamino)-9H-purin-9- yl)cyclohexanecarboxamide 516.3 A437

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,3S)-3-hydroxycycloheptylamino)-9H-purin-9- yl)cyclohexanecarboxamide 534.2 A438

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,3S)-3-hydroxycycloheptylamino)-9H-purin-9- yl)cyclohexanecarboxamide 534   A439

(1S,4s)-4-(2-((1R,3S)-3- hydroxycycloheptylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 566.1 A 440

(1S,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-((1R,3S)-3-hydroxycycloheptylamino)-9H-purin-9- yl)cyclohexanecarboxamide 534.2 A441

(1s,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-(isopropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 455.3 B 442

(1s,4s)-4-(8-(2,6-dichloro-4- (trifluoromethyl)phenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide572.3 C 443

(1s,4s)-4-(8-(2,6-dichloro-3- cyanophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 529.2 A 444

(1R,4s)-4-(2-((1S,3R)-3- hydroxycycloheptylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 566   A 445

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((2S,4R)-2-(hydroxymethyl)tetrahydro-2H-pyran- 4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 536.3 C 446

(1S,4s)-4-(2-((2S,4R)-2- (hydroxymethyl)tetrahydro-2H-pyran-4-ylamino)-8-(2,4,6- trifluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 520.3 A 447

(1s,4s)-4-(8-(3-cyano-2,6- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 497.3 A 448

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1S,3S)-3-hydroxycycloheptylamino)-9H-purin-9- yl)cyclohexanecarboxamide 541.3 A449

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1S,3S)-3-hydroxycycloheptylamino)-9H-purin-9- yl)cyclohexanecarboxamide 557.3 A450

(1s,4s)-4-(2-(2,2-difluoro-3- hydroxypropylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 548.2 A 451

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(2,2-difluoro-3-hydroxypropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 532.2 A 452

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(2,2-difluoro-3-hydroxypropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 532   A 453

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(2,2-difluoro-3-hydroxypropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 516.2 A 454

(1S,4s)-4-(8-(2,6-dichloro-4- (trifluoromethyl)phenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide586.2 B 455

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 543.2 D456

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 527.3 B457

(1S,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 511.4 A458

(1R,4s)-4-(2-((1S,3S)-3- hydroxycyclohexylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.2 A 459

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A460

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A461

(1R,4s)-4-(2-((1S,3S)-3- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.1 A 462

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 A463

(1R,4s)-4-(8-(4-chloro-2,3- difluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.1 A464

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 B465

(1R,4s)-4-(8-(4-chloro-2,5- difluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A466

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,2R)-2-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 A467

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,2R)-2-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.1 A468

(1S,4s)-4-(2-((1R,2R)-2- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.1 A 469

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1R,2R)-2-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 A470

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,2R)-2-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 A471

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((R)-1,1,1-trifluoro-3-hydroxypropan-2-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 550.2 A 472

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((R)-1,1,1-trifluoro-3-hydroxypropan-2-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 557.2 A 473

(1r,4r)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 520.2A 474

(1r,4r)-1-methyl-4-(2-(tetrahydro-2H- pyran-4-ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.2 A 475

(1r,4r)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 543.2 B476

(1r,4r)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide570.2 A 477

(1r,4r)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide554.2 A 478

(1r,4r)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide570.2 A 479

(1r,4r)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide577.2 A 480

(1S,4r)-4-(8-(2,6-dichloro-4- (trifluoromethyl)phenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide 560.2 A 481

(1S,4r)-4-(2-((S)-1-hydroxypropan-2- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide526.2 A 482

(1s,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(3-hydroxy-2,2-dimethylpropylamino)-9H-purin-9- yl)cyclohexanecarboxamide 531.2 A 483

(1S,4s)-4-(2-((1R,2S)-2- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.2 A 484

(1R,4r)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide550.2 A 485

(1r,4r)-4-(2-(cyclopentylamino)-8-(2,6- dichloro-4-cyanophenylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 527.2 B 486

(1r,4r)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(cyclopentylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 511.3B 487

(1r,4r)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-(cyclopentylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 495.2A 488

(1r,4r)-4-(2-(cyclopentylamino)-8-(2,6- dichloro-4-(trifluoromethyl)phenylamino)-9H- purin-9-yl)-1-methylcyclohexanecarboxamide 570.2 A 489

(1r,4r)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(cyclopentylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 504.2A 490

(1r,4r)-4-(2-(cyclopentylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide 536.2 A 491

(1r,4r)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(cyclopentylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 504.3A 492

(1r,4r)-4-(2-(cyclopentylamino)-8-(2,4-dichloro-6-fluorophenylamino)-9H- purin-9-yl)-1-methylcyclohexanecarboxamide 520.2 B 493

(1r,4r)-4-(2-(cyclopentylamino)-8-(2,6-dichloro-4-fluorophenylamino)-9H- purin-9-yl)-1-methylcyclohexanecarboxamide 520.2 A 494

(1r,4r)-4-(2-(cyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxainide 488.3 A 495

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((3S,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 543.3 D 496

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((3R,4S)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 543.2 C 497

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((3R,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 543.3 D 498

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((3S,4S)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 543.3 C 499

(1S,4s)-4-(2-((3S,4R)-3- methyltetrahydro-2H-pyran-4- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.2 D 500

(1R,4s)-4-(2-((3R,4S)-3- methyltetrahydro-2H-pyran-4- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.2 B 501

(1S,4s)-4-(2-((3R,4R)-3- methyltetrahydro-2H-pyran-4- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.2 C 502

(1R,4s)-4-(2-((3S,4S)-3- methyltetrahydro-2H-pyran-4- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.2 C 503

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((3S,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 536.2 D 504

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((3R,4S)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 536.2 B 505

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((3R,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 536.2 C 506

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((3S,4S)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 536.2 C 507

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((3R,4S)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 520.3 A 508

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((3R,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 520.3 B 509

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((3S,4S)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 520.3 B 510

(1R,4s)-4-(2-((3R,4S)-3- methyltetrahydro-2H-pyran-4- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.3 A 511

(1R,4s)-4-(2-((3S,4S)-3- methyltetrahydro-2H-pyran-4- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.3 B 512

(1R,4s)-4-(2-((1S,2R)-2- hydroxycyclohexylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.1 A 513

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1S,2R)-2-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 A514

(1R,4s)-4-(2-((1S,2R)-2- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.1 A 515

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1S,2R)-2-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.1 A516

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1S,2R)-2-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 A517

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1S,2R)-2-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 527.1 A518

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((R)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 515.2 C519

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1S,2R)-2-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 543.2 A520

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((R)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 499.2 C521

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 520.2D 522

(1s,4s)-1-methyl-4-(2-(tetrahydro-2H- pyran-4-ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 552.1 D 523

(1S,4s)-4-(8-(2,6-dichloro-4- (trifluoromethyl)phenylamino)-2-((R)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 558.1 A524

(1s,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 511.2D 525

(1s,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 527.1 D526

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide570.1 D 527

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide554.1 D 528

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide570.1 D 529

(1S,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-((R)-tetrahydrofuran-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 483   A530

(1S,4s)-4-(2-((R)-tetrahydrofuran-3- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 476.2 B 531

(1s,4s)-4-(2-(1-morpholinopropan-2- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 581.1 A 532

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((3S,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 520.3 C 533

(1S,4s)-4-(2-((3S,4R)-3- methyltetrahydro-2H-pyran-4- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 504.3 D 534

(1s,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide577.2 D 535

(1s,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 543.2 D536

(1s,4s)-4-(2-(oxepan-4-ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 504.2B 537

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(oxepan-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 D 538

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(oxepan-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 C 539

(1s,4s)-4-(2-(oxepan-4-ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 554.1D 540

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(oxepan-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 520.2 C 541

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(oxepan-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 536.1 B 542

(1s,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-(oxepan-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 511.2 A 543

(1s,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(oxepan-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 527.2 D 544

(1s,4s)-4-(8-(2,6-dichloro-4- (trifluoromethyl)phenylamino)-2-(oxepan-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 586.2 A 545

(1S,4s)-4-(2-((R)-3,3- difluorocyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 510.3 D 546

(1R,4s)-4-(2-((S)-1-hydroxypropan-2- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide478.2 C 547

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide510.2 D 548

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide494.2 D 549

(1R,4s)-4-(2-((S)-1-hydroxypropan-2- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide526.1 D 550

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide494.1 D 551

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide510.2 D 552

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide501.1 D 553

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide517.2 D 554

(1R,4s)-4-(8-(2,6-dichloro-4- (trifluoromethyl)phenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide 560.1 B 555

(1s,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(oxepan-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 543.2 D 556

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide 488.1 D 557

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,4-dichloro-6-fluorophenylamino)-9H- purin-9-yl)-1-methylcyclohexanecarboxamide 520.1 D 558

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(cyclopentylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 504.3D 559

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(cyclopentylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 504.3C 560

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,6-dichloro-4-fluorophenylamino)-9H- purin-9-yl)-1-methylcyclohexanecarboxamide 520.2 C 561

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,6- dichloro-4-cyanophenylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 527.1 D 562

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,6- dichloro-4-(trifluoromethyl)phenylamino)-9H- purin-9-yl)-1-methylcyclohexanecarboxamide 570.1 A 563

(1S,4s)-4-(2-((1R,3S)-3- hydroxycyclohexylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide518.2 A 564

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide550.2 D 565

(1S,4s)-4-(2-((1R,3S)-3- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide567.1 D 566

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide534.2 C 567

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide550.2 B 568

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide541.2 C 569

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide557.1 D 570

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6- ylamino)-8-(2,6-dichloro-4-(trifluoromethyl)phenylamino)-9H- purin-9-yl)cyclohexanecarboxamide584.2 A 571

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6- ylamino)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 541.2 C 572

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6- ylamino)-8-(2-chloro-4-cyano-6-fluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 525.2 B 573

(1s,4s)-4-(2-(2-oxaspiro[3.3]heptan-6- ylamino)-8-(4-cyano-2,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 509.2 A 574

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide 536   C 575

(1s,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(cyclopentylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 511.2D 576

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide534.2 C 577

(1S,4s)-4-(8-(2,6-dichloro-4- (trifluoromethyl)phenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)- 9H-purin-9-yl)-1-methylcyclohexanecarboxamide 600.1 A 578

(1s,4s)-4-(2-(3,3- difluorocyclobutylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide510.2 D 579

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide526.2 D 580

(1s,4s)-4-(2-(3,3- difluorocyclobutylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide558.2 C 581

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide526.2 D 582

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide542.2 D 583

(1s,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide533.2 D 584

(1s,4s)-4-(8-(2,6-dichloro-4- (trifluoromethyl)phenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide592   A 585

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((S)-3,3-difluorocyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 542.2 B586

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((R)-3,3-difluorocyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 542.2 D587

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((S)-3,3-difluorocyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 526.2 C588

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((R)-3,3-difluorocyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 526.2 D589

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((S)-3,3-difluorocyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 526.2 C590

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((R)-3,3-difluorocyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 526.2 D591

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((S)-3,3-difluorocyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 542.2 C592

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((R)-3,3-difluorocyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 542.2 D593

(1R,4s)-4-(2-((S)-3,3- difluorocyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 510.3 C 594

(1R,4s)-4-(2-((S)-3,3- difluorocyclopentylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 560.2 C 595

(1S,4s)-4-(8-(2,6-dichloro-4- (trifluoromethoxy)phenylamino)-2-((1R,3S)-3-hydroxycyclohexylamino)- 9H-purin-9-yl)cyclohexanecarboxamide602.1 A 596

(1s,4s)-4-(8-(2,6-dichloro-4- (trifluoromethoxy)phenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 622.1 A597

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,6- dichloro-4-(trifluoromethoxy)phenylamino)-9H- purin-9-yl)cyclohexanecarboxamide572.2 A 598

(1s,4s)-4-(2-(cyclobutylamino)-8-(2,6- dichloro-4-(trifluoromethoxy)phenylamino)-9H- purin-9-yl)-1-methylcyclohexanecarboxamide 572.2 A 599

(1s,4s)-4-(2-(cyclobutylamino)-8-(2,6- dichloro-4-cyanophenylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 513.2 D 600

(1s,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(cyclobutylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 497.3 D601

(1s,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-(cyclobutylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 481.3 D602

(1s,4s)-4-(2-(cyclobutylamino)-8-(2,6- dichloro-4-(trifluoromethyl)phenylamino)-9H- purin-9-yl)-1-methylcyclohexanecarboxamide 556   A 603

(1s,4s)-4-(2-(cyclobutylamino)-8- (2,4,6-trichlorophenylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide 522.2 D 604

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(cyclobutylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 490.2 D605

(1s,4s)-4-(2-(cyclobutylamino)-8-(2,4- dichloro-6-fluorophenylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 506.2 D 606

(1s,4s)-4-(2-(cyclobutylamino)-8-(2,6- dichloro-4-fluorophenylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 506.2 D 607

(1s,4s)-4-(2-(cyclobutylamino)-8- (2,4,6-trifluorophenylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide 474.2 D 608

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(cyclobutylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 490   D609

(1R,4s)-4-(2-((1S,3S)-3- hydroxycyclohexylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide518   C 610

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide534   C 611

(1R,4s)-4-(2-((1S,3S)-3- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide566.2 D 612

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide550.1 D 613

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide550.1 D 614

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide534.2 D 615

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide541.3 D 616

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide557.2 D 617

(1S,4s)-4-(2-((1R,3R)-3- hydroxycyclohexylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide518.3 A 618

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide534.2 B 619

(1S,4s)-4-(2-((1R,3R)-3- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide566.2 B 620

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide550.2 B 621

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide550.2 A 622

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide534.2 B 623

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide541.2 C 624

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide557.2 C 625

(1R,4s)-4-(2-((1S,3R)-3- hydroxycyclohexylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide518.2 A 626

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide534.2 B 627

(1R,4s)-4-(2-((1S,3R)-3- hydroxycyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide566.2 D 628

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide550.2 D 629

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 531.2 D 630

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 524.2 D 631

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide550.2 B 632

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide534.2 B 633

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide541   B 634

(1S,4s)-4-(2-((1R,3R)-3- hydroxycyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide504   B 635

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide520   C 636

(1S,4s)-4-(2-((1R,3R)-3- hydroxycyclopentylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide552.2 D 637

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide536.2 D 638

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide536.2 D 639

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide520.2 D 640

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide527.2 D 641

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide543.2 D 642

(1S,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide525.2 A 643

(1R,4s)-4-(2-((1S,3S)-3- hydroxycyclopentylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide504   B 644

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((1S,3S)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide520.2 C 645

(1R,4s)-4-(2-((1S,3S)-3- hydroxycyclopentylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9-yl)- 1-methylcyclohexanecarboxamide552.2 B 646

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((1S,3S)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide536.2 C 647

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((1S,3S)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide536.2 B 648

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((1S,3S)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide520.2 A 649

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1S,3S)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide527.2 C 650

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1S,3S)-3-hydroxycyclopentylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide543.2 C 651

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide542.1 D 652

(1R,4s)-4-(2-(((1S,2S)-2- hydroxycyclohexyl)methylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 518.3A 653

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(((1S,2S)-2-hydroxycyclohexyl)methylamino)-9H- purin-9-yl)cyclohexanecarboxamide534.2 A 654

(1R,4s)-4-(2-(((1S,2S)-2- hydroxycyclohexyl)methylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 566.2A 655

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(((1S,2S)-2-hydroxycyclohexyl)methylamino)-9H- purin-9-yl)cyclohexanecarboxamide550.2 A 656

(1R,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(((1S,2S)-2-hydroxycyclohexyl)methylamino)-9H- purin-9-yl)cyclohexanecarboxamide550.2 A 657

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(((1S,2S)-2-hydroxycyclohexyl)methylamino)-9H- purin-9-yl)cyclohexanecarboxamide534.2 A 658

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(((1S,2S)-2-hydroxycyclohexyl)methylamino)-9H- purin-9-yl)cyclohexanecarboxamide541.3 A 659

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(((1S,2S)-2-hydroxycyclohexyl)methylamino)-9H- purin-9-yl)cyclohexanecarboxamide557.2 A 660

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(((1S,2R)-2-hydroxycyclohexyl)methylamino)-9H- purin-9-yl)cyclohexanecarboxamide534.2 A 661

(1R,4s)-4-(2-(((1S,2R)-2- hydroxycyclohexyl)methylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 566.2A 662

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(((1S,2R)-2-hydroxycyclohexyl)methylamino)-9H- purin-9-yl)cyclohexanecarboxamide550.2 A 663

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(((1S,2R)-2-hydroxycyclohexyl)methylamino)-9H- purin-9-yl)cyclohexanecarboxamide534   A 664

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-(((1S,2R)-2-hydroxycyclohexyl)methylamino)-9H- purin-9-yl)cyclohexanecarboxamide541.2 A 665

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(((1S,2R)-2-hydroxycyclohexyl)methylamino)-9H- purin-9-yl)cyclohexanecarboxamide557.2 A 666

(1s,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(3,3-difluorocyclobutylamino)-9H-purin-9- yl)-1-methylcyclohexanecarboxamide549.2 D 667

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(4-(2,5-dioxopyrrolidin-1-yl)cyclohexylamino)-9H-purin-9-yl)cyclohexanecarboxamide 617.1 A 668

(1s,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(4-(2,5-dioxopyrrolidin-1-yl)cyclohexylamino)-9H-purin-9-yl)cyclohexanecarboxamide 624.2 A 669

(1R,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 515.2 B 670

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxainide 531.2 D 671

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 524.2 D 672

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 524.2 D 673

(1s,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 520.1D 674

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 536.1 D675

(1s,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)-1- methylcyclohexanecarboxamide 536.1 D676

(1s,4s)-4-(2-(4-(1,2,4-oxadiazol-5-yl)cyclohexylamino)-8-(2,4-dichloro-6- fluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 558.1 A 677

(1s,4s)-4-(2-(4-(1,2,4-oxadiazol-5- yl)cyclohexylamino)-8-(2-chloro-4,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 572.1 A 678

(1s,4s)-4-(2-(4-(1,2,4-oxadiazol-5- yl)cyclohexylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 604.1 A 679

(1s,4s)-4-(2-(4-(1,2,4-oxadiazol-5-yl)cyclohexylamino)-8-(2,6-dichloro-4- fluorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 588.1 A 680

(1s,4s)-4-(2-(4-(1,2,4-oxadiazol-5- yl)cyclohexylamino)-8-(2-chloro-4-cyano-6-fluorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 579.2 A681

(1s,4s)-4-(2-(4-(1,2,4-oxadiazol-5-yl)cyclohexylamino)-8-(2,6-dichloro-4- cyanophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 595.1 A 682

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 513   D683

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1R,3R)-3-hydroxycyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 529.2 D684

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 543.2 B685

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1R,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 527.1 B686

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 543.2 B687

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 527.1 A688

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 543.2 C689

(1R,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((1S,3S)-3-hydroxycyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 527.1 C690

(1s,4s)-4-(8-(4-bromo-2,6- dichlorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 584   D 691

(1s,4s)-4-(8-(4-bromo-2,6- dichlorophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 618   B692

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 524.2 D 693

(1s,4s)-4-(2-(cyclopentylamino)-8-(2,3- dichloro-4-cyanophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 513.2 A 694

(1R,4s)-4-(8-(2,3-dichloro-4- cyanophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 503.2 A695

(1s,4s)-4-(8-(2,3-dichloro-4- cyanophenylamino)-2-(4,4-difluorocyclohexylamino)-9H-purin-9- yl)cyclohexanecarboxamide 563.2 A696

(1s,4s)-4-(8-(2,3-dichloro-4- cyanophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 529.2 B 697

(1S,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-((R)-3,3-difluorocyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 517.2 C698

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((R)-3,3-difluorocyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 553.2 D699

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((R)-3,3-difluorocyclopentylamino)-9H-purin-9- yl)cyclohexanecarboxamide 549.2 C700

(1S,4s)-4-(2-((R)-1- (methylsulfonyl)piperidin-3-ylamino)-8-(2,4,6-trichlorophenylamino)-9H- purin-9-yl)cyclohexanecarboxamide615.2 B 701

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((R)-1-(methylsulfonyl)piperidin-3-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 599.2 B 702

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((R)-1-(methylsulfonyl)piperidin-3-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 606.2 A 703

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((R)-1-(methylsulfonyl)piperidin-3-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 583.2 A 704

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((R)-1-(methylsulfonyl)piperidin-3-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 590.2 A 705

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4,6-trichlorophenylamino)-9H-purin-2- ylamino)-N-methylpiperidine-1-carboxamide 594.6 A 706

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4-dichloro-6-fluorophenylamino)-9H-purin-2- ylamino)-N-methylpiperidine-1-carboxamide 578.2 A 707

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-2- ylamino)-N-methylpiperidine-1-carboxamide 585.2 A 708

(R)-methyl-1-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 586.2 C709

(R)-methyl-1-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2-chloro-4-cyano-6-fluorophenylamino)-9H-purin- 2-ylamino)piperidine-1-carboxylate570.2 B 710

(1S,4s)-4-(2-((R)-1-acetylpiperidin-3- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 579.2 A 711

(1S,4s)-4-(2-((R)-1-acetylpiperidin-3- ylamino)-8-(2,4-dichloro-6-fluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 563.2 A 712

(1S,4s)-4-(2-((R)-1-acetylpiperidin-3- ylamino)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 570.2 A 713

(1S,4s)-4-(2-((R)-1-acetylpiperidin-3- ylamino)-8-(4-chloro-2,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 547.2 A 714

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 540.2 D 715

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)- 9H-purin-9-yl)-1-methylcyclohexanecarboxamide 538.2 D 716

(1R,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)- 9H-purin-9-yl)-1-methylcyclohexanecarboxamide 554.2 D 717

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((3S,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide 550.2 D 718

(1S,4s)-4-(2-((3S,4R)-3- fluorotetrahydro-2H-pyran-4-ylamino)-8-(2,4,6-trichlorophenylamino)-9H- purin-9-yl)-1-methylcyclohexanecarboxamide 570.1 D 719

(1R,4s)-4-(2-((3S,4S)-3- fluorotetrahydro-2H-pyran-4-ylamino)-8-(2,4,6-trichlorophenylamino)-9H- purin-9-yl)-1-methylcyclohexanecarboxamide 570.1 D 720

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)- 9H-purin-9-yl)-1-methylcyclohexanecarboxamide 538.2 D 721

(1R,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)- 9H-purin-9-yl)-1-methylcyclohexanecarboxamide 538.2 D 722

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((3S,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide 534.2 D 723

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((3S,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 520.2 D 724

(1R,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)- 9H-purin-9-yl)-1-methylcyclohexanecarboxamide 538.2 D 725

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((3S,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide 535.2 D 726

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)- 9H-purin-9-yl)-1-methylcyclohexanecarboxamide 554.2 D 727

(1S,4s)-1-methyl-4-(2-((3S,4R)-3- methyltetrahydro-2H-pyran-4-ylamino)-8-(2,4,6- trichlorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 566.2 D 728

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 540.2 D 729

(1s,4s)-4-(2-(3- (methylsulfonyl)cyclobutylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 586  A 730

(1s,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-(3-(methylsulfonyl)cyclobutylamino)-9H- purin-9-yl)cyclohexanecarboxamide577.2 A 731

(1s,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-(3-(methylsulfonyl)cyclobutylamino)-9H- purin-9-yl)cyclohexanecarboxamide570.2 A 732

(1S,4s)-4-(2-((R)-1-ethylpiperidin-3- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 567.2 A 733

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((R)-1-ethylpiperidin-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 556.2 A734

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((R)-1-ethylpiperidin-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 549.2 A735

(1s,4s)-4-(8-(2,6-dichloro-4- (trifluoromethyl)phenylamino)-2-(3-(methylsulfonyl)cyclobutylamino)-9H- purin-9-yl)cyclohexanecarboxamide620.2 A 736

(1s,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-(3-(methylsulfonyl)cyclobutylamino)-9H- purin-9-yl)cyclohexanecarboxamide554   A 737

(1S,4s)-4-(8-(2,6-dichloro-4- (trifluoromethyl)phenylamino)-2-((R)-1-ethylpiperidin-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 599.2A 738

(1S,4s)-4-(2-((R)-1-isopropylpiperidin- 3-ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 579.2 A 739

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((R)-1-isopropylpiperidin-3-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide570.2 A 740

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((R)-1-isopropylpiperidin-3-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide547.2 A 741

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((R)-1-isopropylpiperidin-3-ylamino)-9H- purin-9-yl)cyclohexanecarboxamide563.2 A 742

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((R)-1-phenylpiperidin-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 581.2 A743

(1S,4s)-4-(2-((R)-1-phenylpiperidin-3- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 613.2 A 744

(1S,4s)-4-(8-(2,6-dichloro4- cyanophenylamino)-2-((R)-1-phenylpiperidin-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 604.2 A745

(1S,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-((R)-1-phenylpiperidin-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 572.2 A746

(1S,4s)-4-(2-((R)-1-phenylpiperidin-3- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 566.2 A 747

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((R)-1-phenylpiperidin-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 581.2 A748

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((R)-1-phenylpiperidin-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 597.2 A749

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((R)-1-phenylpiperidin-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 597.2 A750

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((R)-1-phenylpiperidin-3-ylamino)-9H-purin- 9-yl)cyclohexanecarboxamide 588.2 A751

(1S,4s)-4-(2-((R)-1-benzylpiperidin-3- ylamino)-8-(2-chloro-4,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 595.2 A 752

(1S,4s)-4-(2-((R)-1-benzylpiperidin-3- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 629.2 A 753

(1S,4s)-4-(2-((R)-1-benzylpiperidin-3- ylamino)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 618.2 A 754

(1S,4s)-4-(2-((R)-1-benzylpiperidin-3- ylamino)-8-(2,6-dichloro-4-(trifluoromethyl)phenylamino)-9H- purin-9-yl)cyclohexanecarboxamide661.2 A 755

(iS,4s)-4-(2-((R)-1-benzylpiperidin-3- ylamino)-8-(4-cyano-2,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 586.4 A 756

(1S,4s)-4-(2-((R)-1-benzylpiperidin-3- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 579.2 A 757

(1S,4s)-4-(2-((R)-1-benzylpiperidin-3- ylamino)-8-(4-chloro-2,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 595.2 A 758

(1S,4s)-4-(2-((R)-1-benzylpiperidin-3- ylamino)-8-(2,4-dichloro-6-fluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 611.2 A 759

(1S,4s)-4-(2-((R)-1-benzylpiperidin-3- ylamino)-8-(2,6-dichloro-4-fluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 611.2 A 760

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)- 9H-purin-9-yl)-1-methylcyclohexanecarboxamide 561.2 D 761

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)- 9H-purin-9-yl)-1-methylcyclohexanecarboxamide 561.2 D 762

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 547.2 D 763

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((3S,4R)-3-methyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide 557.2 D 764

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((R)-3,3-dimethyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 551.2 B 765

(1R,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 548.1 D 766

(1S,4s)-4-(2-((R)-3,3- dimethyltetrahydro-2H-pyran-4- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 567.2 B 767

(R)-isopropyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2-chloro-4,6-difluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 591.2A 768

(R)-isopropyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4,6-trichlorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 623.2B 769

(R)-isopropyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 614.2 B770

(R)-isopropyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-dichloro-4-(trifluoromethyl)phenylamino)-9H- purin-2-ylamino)piperidine-1-carboxylate 657.2 A 771

(R)-isopropyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(4-cyano-2,6-difluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 582.2A 772

(R)-isopropyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 575.2A 773

(R)-isopropyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(4-chloro-2,6-difluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 591.2B 774

(R)-isopropyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4-dichloro-6-fluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 607.2C 775

(R)-isopropyl 3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-dichloro-4-fluorophenylamino)-9H-purin-2- ylamino)piperidine-1-carboxylate 607.2A 776

(R)-isopropyl 3-(9-((1S,4S)-4- carbamoylcyclohexyl)-8-(2-chloro-4-cyano-6-fluorophenylamino)-9H-purin- 2-ylamino)piperidine-1-carboxylate582.2 B 777

(1S,4s)-4-(2-((R)-1-benzylpiperidin-3- ylamino)-8-(2-chloro-4-cyano-6-fluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 602.2 A 778

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2-chloro-4,6-difluorophenylamino)-9H-purin-2- ylamino)-N-phenylpiperidine-1-carboxamide 624.2 A 779

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4,6-trichlorophenylamino)-9H-purin-2- ylamino)-N-phenylpiperidine-1-carboxamide 656.2 B 780

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-2- ylamino)-N-phenylpiperidine-1-carboxamide 647.2 A 781

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2- ylamino)-N-phenylpiperidine-1-carboxamide 608.2 A 782

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(4-chloro-2,6-difluorophenylamino)-9H-purin-2- ylamino)-N-phenylpiperidine-1-carboxamide 624.2 A 783

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,4-dichloro-6-fluorophenylamino)-9H-purin-2- ylamino)-N-phenylpiperidine-1-carboxamide 640.2 A 784

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-dichloro-4-fluorophenylamino)-9H-purin-2- ylamino)-N-phenylpiperidine-1-carboxamide 640.2 A 785

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2-chloro-4-cyano-6-fluorophenylamino)-9H-purin- 2-ylamino)-N-phenylpiperidine-1-carboxamide 631.2 A 786

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((R)-3,3-dimethyltetrahydro-2H-pyran-4- ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 535.2 A 787

(1S,4s)-4-(8-(2-chloro-4,6- difluorophenylamino)-2-((R)-1-tosylpiperidin-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 659.2 A788

(1S,4s)-4-(2-((R)-1-tosylpiperidin-3- ylamino)-8-(2,4,6-trichlorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 691.2 A 789

(1S,4s)-4-(8-(2,6-dichloro-4- cyanophenylamino)-2-((R)-1-tosylpiperidin-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 682.2 A790

(1S,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-((R)-1-tosylpiperidin-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 650.2 A791

(1S,4s)-4-(2-((R)-1-tosylpiperidin-3- ylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 643.2 A 792

(1S,4s)-4-(8-(4-chloro-2,6- difluorophenylamino)-2-((R)-1-tosylpiperidin-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 659.2 A793

(1S,4s)-4-(8-(2,4-dichloro-6- fluorophenylamino)-2-((R)-1-tosylpiperidin-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 675.2 A794

(1S,4s)-4-(8-(2,6-dichloro-4- fluorophenylamino)-2-((R)-1-tosylpiperidin-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 675.2 A795

(1S,4s)-4-(8-(2-chloro-4-cyano-6- fluorophenylamino)-2-((R)-1-tosylpiperidin-3-ylamino)-9H-purin-9- yl)cyclohexanecarboxamide 666.2 A796

(R)-3-(9-((1s,4S)-4- carbamoylcyclohexyl)-8-(2,6-dichloro-4-(trifluoromethyl)phenylamino)-9H- purin-2-ylamino)-N-methylpiperidine-1-carboxamide 628.2 A 797

(1S,4s)-4-(2-((R)-1-acetylpiperidin-3- ylamino)-8-(2-chloro-4,6-difluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 547.2 A 798

(1S,4s)-4-(2-((R)-1-acetylpiperidin-3- ylamino)-8-(2,6-dichloro-4-(trifluoromethyl)phenylamino)-9H- purin-9-yl)cyclohexanecarboxamide613.2 A 799

(1S,4s)-4-(2-((R)-1-acetylpiperidin-3- ylamino)-8-(2,6-dichloro-4-fluorophenylamino)-9H-purin-9- yl)cyclohexanecarboxamide 563.2 A 800

(1S,4s)-4-(2-((R)-1-acetylpiperidin-3-ylamino)-8-(2,6-dichlorophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide 545.2 A 801

(1S,4s)-4-(8-(4-cyano-2,6- difluorophenylamino)-2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide 515.3 D 802

(1R,4s)-4-(2-(((3R,4S)-3- fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6- trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide 571.0 D

A number of references have been cited, the disclosures of which areincorporated herein by reference in their entirety.

What is claimed is:
 1. A method for treating melanoma, comprisingadministering to a patient having melanoma an effective amount of acompound of formula (I):

or a pharmaceutically acceptable salt, tautomer, stereoisomer orenantiomer thereof, wherein: R¹ is substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylalkyl, or substituted or unsubstitutednon-aromatic heterocyclyl; R² is H or substituted or unsubstituted C₁₋₃alkyl; R³ is phenyl, substituted with one or more halogen, optionallyfurther substituted with one or more substituents independently selectedfrom substituted or unsubstituted C₁₋₃ alkyl, CN, and —OR′, wherein eachR′ is independently substituted or unsubstituted C₁₋₃ alkyl; whereinwhen an alkyl group is substituted, it is substituted with a substituentselected from the group consisting of chloro; iodo; bromo; fluoro;alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro;cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine;aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl;sulfinyl; sulfone; sulfonamide; acyl; ester; urea; urethane; oxime;hydroxyl amine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide;hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate;cyanate; thiocyanate; B(OH)₂; and O(alkyl)aminocarbonyl; wherein when agroup other than an alkyl group is substituted, it is substituted with asubstituent selected from the group consisting of chloro; iodo; bromo;fluoro; alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino;carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine;guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine;thiocarbonyl; sulfinyl; sulfone; sulfonamide; acyl; ester; urea;urethane; oxime; hydroxylamine; alkoxyamine; aryloxyamine;aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide;isocyanate; isothiocyanate; cyanate; thiocyanate; oxo; B(OH)₂,O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused ornon-fused polycyclic, or a heterocyclyl, which may be monocyclic orfused or non-fused polycyclic; monocyclic or fused or non-fusedpolycyclic aryl or heteroaryl; aryloxy; aralkyloxy; heterocyclyloxy; andheterocyclylalkoxy; and provided that the compound is not4-[2-[(1-methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide,or4-[8-[(2,4-difluorophenyl)amino]-2-[(trans-4-hydroxycyclohexyl)amino]-9H-purin-9-yl]-cis-cyclohexanecarboxamide,wherein said compound of formula (I) is administered to said patient inan amount of about 1 mg/day to about 1400 mg/day.
 2. The method of claim1, wherein said compound of formula (I) is administered to said patientin an amount of about 10 mg/day to about 1400 mg/day, about 100 mg/dayto about 1400 mg/day, about 400 mg/day to about 1400 mg/day, about 600mg/day to about 1400 mg/day, about 750 mg/day to about 1400 mg/day orabout 750 mg/day to about 1350 mg/day.
 3. The method of claim 1, whereinsaid compound of formula (I) is administered to said patient in a unitdosage formulation that comprises between about 1 mg and 200 mg, about35 mg and about 1400 mg, about 125 mg and about 1400 mg, about 250 mgand about 1400 mg, about 500 mg and about 1400 mg or about 750 mg andabout 1350 mg of said compound of formula (I).
 4. The method of claim 1,wherein said compound of formula (I) is administered to said patient ina unit dosage formulation that comprises 1 mg, 5 mg, 10 mg, 20 mg, 30mg, 35 mg, 50 mg, 70 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,500 mg, 560 mg, 700 mg, 750 mg, 900 mg, 1000 mg, 1150, 1350 or 1400 mgof said compound of formula (I).
 5. The method of claim 1, wherein saidcompound of formula (I) is administered to said patient once, twice,three, four or more times daily.
 6. The method of claim 1, wherein saidcompound of formula (I) is administered to said patient in an amount ofabout 750 mg/day, about 900 mg/day, about 1150 mg/day or about 1350mg/day.
 7. The method of claim 1, wherein said compound of formula (I)is administered to said patient in an amount of about 750 mg/day.
 8. Themethod of claim 1, wherein said compound of formula (I) is administeredto said patient in an amount of about 900 mg/day.
 9. The method of claim1, wherein said compound of formula (I) is administered to said patientin an amount of about 1150 mg/day.
 10. The method of claim 1, whereinsaid compound of formula (I) is administered to said patient in anamount of about 1350 mg/day.
 11. The method of claim 1, wherein R¹ isoxetanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydro-thiopyrandioxide, piperidyl, oxepanyl, or oxaspiroheptyl,optionally substituted with one or more substituents independentlyselected from F, OH, SO₂CH₃, SO₂-tosyl, C(═O)CH₃, C(═O)OCH₃,C(═O)O-tert-butyl, C(═O)O-isopropyl, C(═O)NHCH₃, C(═O)NH-phenyl, methyl,ethyl, isopropyl, CH₂OH, phenyl, pyridyl, or benzyl.
 12. The method ofclaim 1, wherein R² is CH₃.
 13. The method of claim 1, wherein R³ is2,4,6-trihalogen substituted phenyl.
 14. The method of claim 1, whereinthe compound is(1s,4s)-4-(8-(3-chlorophenylamino)-2-(isopropylamino)-9H-purin-9-yl)cyclohexanecarboxamide.15. The method of claim 1, wherein the compound is(1R,4s)-4-(8-(2,4-dichloro-6-fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide.16. The method of claim 1, wherein the compound is(1R,4s)-4-(8-(2,4-dichloro-6-fluorophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide.
 17. The method ofclaim 1, wherein the compound is(1R,4s)-4-(8-(2,6-dichloro-4-cyanophenylamino)-2-((S)-1-hydroxypropan-2-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide.18. The method of claim 1, wherein the compound is(1s,4s)-4-(2-(cyclobutylamino)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide.19. The method of claim 1, wherein the compound is(1s,4s)-4-(2-(cyclobutylamino)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide.20. The method of claim 1, wherein the compound is(1s,4s)-4-(2-(3,3-difluorocyclobutylamino)-8-(2,4,6-trifluorophenylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide.21. The method of claim 1, wherein the compound is(1s,4s)-4-(2-(cyclopentylamino)-8-(2,6-dichloro-4-cyanophenylamino)-9H-purin-9-yl)cyclohexanecarboxamide.22. The method of claim 1, wherein the compound is(1S,4s)-4-(8-(2,6-dichloro-4-fluorophenylamino)-2-((R)-3,3-difluorocyclopentylamino)-9H-purin-9-yl)cyclohexanecarboxamide.23. The method of claim 1, wherein the compound is(1R,4s)-4-(2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.24. The method of claim 1, wherein the compound is(1R,4s)-4-(8-(2,4-dichloro-6-fluorophenylamino)-2-((1S,3R)-3-hydroxycyclohexylamino)-9H-purin-9-yl)-1-methylcyclohexanecarboxamide.25. The method of claim 1, wherein the compound is(1S,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.26. The method of claim 1, wherein the compound is(1S,4s)-4-(8-((4-chloro-2,6-difluorophenyl)amino)-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.27. The method of claim 1, wherein the compound is(1s,4s)-4-(8-((4-chloro-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.